Principles and Practice of Cancer Infectious Diseases (Current Clinical Oncology)

Principles and Practice of Cancer Infectious Diseases

Current Clinical Oncology Maurie Markman, MD, Series Editor

For other titles published in this series, go to www.springer.com/series/7631

Amar Safdar Editor

Principles and Practice of Cancer Infectious Diseases

Editor Amar Safdar Department of Infectious Diseases, Infection Control, and Employee Health The University of Texas M.D. Anderson Cancer Center Houston, TX USA [email protected]

ISBN 978-1-60761-643-6 e-ISBN 978-1-60761-644-3 DOI 10.1007/978-1-60761-644-3 Springer New York Dordrecht Heidelberg London Library of Congress Control Number: 2011928679 © Springer Science+Business Media, LLC 2011 All rights reserved. This work may not be translated or copied in whole or in part without the written permission of the publisher (Humana Press, c/o Springer Science+Business Media, LLC, 233 Spring Street, New York, NY 10013, USA), except for brief excerpts in connection with reviews or scholarly analysis. Use in connection with any form of information storage and retrieval, electronic adaptation, computer software, or by similar or dissimilar methodology now known or hereafter developed is forbidden. The use in this publication of trade names, trademarks, service marks, and similar terms, even if they are not identified as such, is not to be taken as an expression of opinion as to whether or not they are subject to proprietary rights. While the advice and information in this book are believed to be true and accurate at the date of going to press, neither the authors nor the editors nor the publisher can accept any legal responsibility for any errors or omissions that may be made. The publisher makes no warranty, express or implied, with respect to the material contained herein. Printed on acid-free paper Humana Press is part of Springer Science+Business Media (www.springer.com)

This book is dedicated for promoting excellence in care and well-being for the patients with cancer.

wwwwwwwwwwwwwwwwww

Preface

Patients with cancer are highly susceptible to infections. These infections are inclined to be difficult to prevent, diagnose, and treat. There are a variety of reasons for this which will be discussed in detail in the chapters of this book. The intent for this book is to provide a comprehensive review of the ever changing spectrum of the management of infectious diseases in this complex population of patients. The changes in patient demography, near-constant global migration of contagious infections, emerging resistance to standard antimicrobial therapy, and the impact of expanding repertoire of antineoplastic therapies including the anticancer biologics and stem cell transplantation have influenced these changes. This book will provide a detailed guide for assessment of risk factors for various infections, evaluating prognosis among susceptible oncology patients with complex issues related to management of opportunistic infections. Strategies to promote hosts’ immune response underscore the future measures based on perspicacious insight in the disease pathogenesis; interaction between the pathogen and host’s immune function and inflammatory response are given prominent discussion throughout the book. I hope the reader will become acquainted with common and less often encountered infections and importantly, develop a keen knowledge of conditions that might be mistaken as infectious diseases in patients undergoing treatment for neoplastic diseases. Houston, TX, USA

Amar Safdar, MD

vii

wwwwwwwwwwwwwwwwww

Contents

Part I  Overview and Special Population   1  Infections in Patients with Cancer: Overview....................................................... Amar Safdar, Gerald Bodey, and Donald Armstrong

3

  2  Infections in Hematopoietic Stem Cell Transplant Recipients............................ Georg Maschmeyer and Per Ljungman

17

  3  Infections in Patients with Hematologic Malignancies......................................... Genovefa Papanicolaou and Jayesh Mehta

27

  4  Infections in Solid Tumor Patients......................................................................... Alison G. Freifeld

39

  5  Infections in Patients with Hematologic Malignancies Treated with Monoclonal Antineoplastic Therapy............................................... André Goy and Susan O’Brien

47

  6  Postsurgery Infections in Cancer Patients............................................................. Emilio Bouza, Almudena Burillo, Juan Carlos Lopez-Gutierrez, and José F. Tomás-Martinez

67

  7  Management of Infections in Critically Ill Cancer Patients................................ Henry Masur

87

Part II  Clinical Syndromes   8  Management of the Neutropenic Patient with Fever............................................ Kenneth V.I. Rolston and Gerald P. Bodey

95

  9  Controversies in Empiric Therapy of Febrile Neutropenia................................. 105 John R. Wingard 10  Catheter-Related Infections in Cancer Patients.................................................... 113 Iba Al Wohoush, Anne-Marie Chaftari, and Issam Raad 11  Intravascular Device-Related Infections: Catheter Salvage Strategies and Prevention of Device-Related Infection........................................ 123 Nasia Safdar and Dennis G. Maki 12  Pneumonia in the Cancer Patient........................................................................... 143 Scott E. Evans and Amar Safdar

ix

x

13  Noninfectious Lung Infiltrates That May Be Confused with Pneumonia in the Cancer Patient.................................................................. 153 Rana Kaplan, Lara Bashoura, Vickie R. Shannon, Burton F. Dickey, and Diane E. Stover 14  Mucosal Barrier Injury and Infections.................................................................. 167 Nicole M.A. Blijlevens and J. Peter Donnelly 15  Bacterial Colonization and Host Immunity........................................................... 175 Coralia N. Mihu, Karen J. Vigil, and Javier A. Adachi 16  Neutropenic Enterocolitis and Clostridium difficile Infections............................ 181 Amar Safdar, Bruno P. Granwehr, Stephen A. Harold, and Herbert L. DuPont 17  Management of Reactivation of Hepatitis B and Hepatitis C During Antineoplastic Therapy.............................................................................. 189 Marta Davila and Harrys A. Torres 18  Management of Genitourinary Tract Infections................................................... 195 Amar Safdar and Maurie Markman 19  Central Nervous System Infections in Cancer Patients........................................ 207 Victor Mulanovich and Amar Safdar 20  Endocarditis in Oncology Patients......................................................................... 219 Sara E. Cosgrove and Aruna Subramanian 21  Skin Disorders Difficult to Distinguish from Infection......................................... 233 Sharon Hymes, Susan Chon, and Ana Ciurea Part III  Major Etiologic Agents 22  Overview of Invasive Fungal Disease in Oncology Patients................................. 257 Amar Safdar 23  Diagnosis of Invasive Fungal Disease..................................................................... 261 Dionissios Neofytos and Kieren Marr 24  Invasive Candidiasis in Management of Infections in Cancer Patients.................................................................................................... 273 Matteo Bassetti, Malgorzata Mikulska, Juan Gea-Banacloche, and Claudio Viscoli 25  Management of Aspergillosis, Zygomycosis, and Other Clinically Relevant Mold Infections....................................................................... 283 Konstantinos Leventakos and Dimitrios P. Kontoyiannis 26  Cryptococcal Disease and Endemic Mycosis......................................................... 293 Johan A. Maertens and Hélène Schoemans 27  Current Controversies in the Treatment of Fungal Infections............................ 301 Christopher D. Pfeiffer, John R. Perfect, and Barbara D. Alexander

Contents

Contents

xi

28  Fungal Drug Resistance and Pharmacologic Considerations of Dosing Newer Antifungal Therapies.................................................................. 317 Russell E. Lewis and David S. Perlin 29  Immunotherapy for Difficult-to-Treat Invasive Fungal Diseases........................ 331 Brahm H. Segal, Amar Safdar, and David A. Stevens 30  Cytomegalovirus in Patients with Cancer............................................................. 341 Morgan Hakki, Per Ljungman, and Michael Boeckh 31  Epstein-Barr Virus, Varicella Zoster Virus, and Human Herpes Viruses-6 and -8..................................................................... 359 Mini Kamboj and David M. Weinstock 32  Respiratory Viruses................................................................................................. 371 Roy F. Chemaly, Dhanesh B. Rathod, and Robert Couch 33  BK, JC, and Parvovirus Infections in Patients with Hematologic Malignancies.............................................................................. 387 Véronique Erard and Michael Boeckh 34  Antiviral Resistance and Implications for Prophylaxis........................................ 397 Robin K. Avery 35  Management of Gram-Positive Bacterial Disease: Staphylococcus aureus, Streptococcal, Pneumococcal, and Enterococcal Infections.................................................................................... 409 Samuel Shelburne and Daniel M. Musher 36  Infections Caused by Aerobic and Anaerobic Gram-Negative Bacilli............................................................................................. 423 Kenneth V.I. Rolston, David E. Greenberg, and Amar Safdar 37  Listeriosis and Nocardiosis..................................................................................... 435 Heather E. Clauss and Bennett Lorber 38  Antibacterial Distribution and Drug–Drug Interactions in Cancer Patients.................................................................................................... 443 Ursula Theuretzbacher and Markus Zeitlinger 39  Mycobacterium tuberculous Infection..................................................................... 455 Michael Glickman 40  Nontuberculous Mycobacterial Infections............................................................. 463 Amar Safdar 41  Parasitic Infections in Cancer Patients: Toxoplasmosis, Strongyloidiasis, and Other Parasites......................................... 469 Brian G. Blackburn and José G. Montoya 42  Zoonoses in Cancer Patients................................................................................... 481 Donald Armstrong

xii

Part IV  Management of Antimicrobial Therapy 43  Antimicrobial Stewardship: Considerations for a Cancer Center...................... 491 Coralia N. Mihu, Alla Paskovaty, and Susan K. Seo 44  Controversies in Antimicrobial Stewardship........................................................ 499 Graeme N. Forrest 45  Prevention of Antimicrobial Resistance: Current and Future Strategies.............................................................................................. 507 Cesar A. Arias and Adolf W. Karchmer Part V  Infection Prevention: Antimicorbial Prophylaxis and Immunization 46  Antibacterial, Antifungal, and Antiviral Prophylaxis in High-Risk Cancer and Stem Cell Transplant Population................................ 521 Marcio Nucci and John R. Wingard 47  Controversies in Antimicrobial Prophylaxis......................................................... 533 Ben de Pauw and Marta Stanzani 48  Infection Prevention – Protected Environment and Infection Control.............................................................................................. 541 J. Peter Donnelly 49  Prevention of Tropical and Parasitic Infections: The Immunocompromised Traveler....................................................................... 551 Francesca F. Norman and Rogelio López-Vélez 50  Prophylactic Vaccination of Cancer Patients and Hematopoietic Stem Cell Transplant Recipients........................................... 561 William Decker and Amar Safdar Index.................................................................................................................................. 573

Contents

Contributors

Javier A. Adachi, M.D. Department of Infectious Diseases, The University of Texas M.D. Anderson Cancer Center, Houston, TX, USA Barbara D. Alexander, M.D. Department of Medicine, Division of Infectious Diseases and International Health, Duke University Medical Center, Durham, NC, USA Iba Al Wohoush, M.D. Infectious Diseases, Infection Control, and Employee Health, The University of Texas M.D. Anderson Cancer Center, Houston, Texas, USA Cesar A. Arias, M.D. Department of Internal Medicine, Division of Infectious Diseases, University of Texas Medical School at Houston, TX, USA Donald Armstrong, M.D. Department of Medicine, Infectious Disease Service, Memorial Sloan–Kettering Cancer Center, New York, NY, USA Robin K. Avery, M.D. Department of Infectious Disease, Cleveland Clinic Foundation, Lerner College of Medicine of Case Western Reserve University, Cleveland, OH, USA Lara Bashoura, M.D. Department of Pulmonary Medicine, The University of Texas M.D. Anderson Cancer Center, Houston, TX, USA Matteo Bassetti, M.D., Ph.D. Division of Infectious Diseases, San Martino Hospital and University of Genoa, Genoa, Italy Brian G. Blackburn, M.D. Department of Internal Medicine, Division of Infectious Diseases and Geographic Medicine, Stanford University School of Medicine, Stanford, CA, USA Nicole M. A. Blijlevens, M.D. Department of Haematology, Radboud University Nijmegen Medical Centre & Nijmegen University Centre for Infectious Diseases, Nijmegen, The Netherlands Gerald P. Bodey, M.D. Department of Infectious Diseases, Infection Control, and Employee Health, The University of Texas M.D. Anderson Cancer Center, Houston, TX, USA

xiii

xiv

Michael Boeckh, M.D. Vaccine and Infectious Disease Division, University of Washington, Fred Hutchinson Cancer Research Center, Seattle, WA, USA Emilio Bouza, M.D. Clinical Microbiology and Infectious Diseases Department, Hospital General Universitario Gregorio Marañón, Universidad Complutense de Madrid; CIBER de Enfermedades Respiratorias (CIBERES), Madrid, Spain Almudena Burrillo, M.D., Ph.D. Clinical Microbiology Department, Hospital Universitario de Móstoles, Madrid, Spain Anne-Marie Chaftari, M.D. Department of Infectious Diseases, Infection Control, and Employee Health, The University of Texas M.D. Anderson Cancer Center, Houston, TX, USA Roy F. Chemaly, M.D. Department of Infectious Diseases, Infection Control, and Employee Health, The University of Texas M.D. Anderson Cancer Center, Houston, TX, USA Susan Chon, M.D. Department of Dermatology, The University of Texas M.D. Anderson Cancer Center, Houston, TX, USA Ana Ciurea, M.D. Department of Dermatology, The University of Texas M.D. Anderson Cancer Center, Houston, TX, USA Heather E. Clauss, M.D. Department of Infectious Diseases, Temple University Hospital, Philadelphia, PA, USA Sara E. Cosgrove, M.D. Division of Infectious Diseases, Johns Hopkins University School of Medicine, Baltimore, MD, USA Robert Couch, M.D. Department of Molecular Virology and Microbiology, Baylor College of Medicine, Center for Infection and Immunity Research, Houston, TX, USA Marta Davila, M.D. Department of Gastroenterology, Hepatology, and Nutrition, The University of Texas M.D. Anderson Cancer Center, Houston, TX, USA William Decker, Ph.D. Department of Blood and Marrow Transplantation, The University of Texas M.D. Anderson Cancer Center, Houston, TX, USA Burton F. Dickey, M.D. Department of Pulmonary Medicine, The University of Texas M.D. Anderson Cancer Center, Houston, TX, USA J. Peter Donnelly, Ph.D. Department of Haematology and Nijmegen Institute for Infection, Inflammation and Immunity, Radboud University Nijmegen Medical Centre, Nijmegen, The Netherlands

Contributors

Contributors

xv

Herbert L. DuPont, M.D. Department of Medicine, The University of Texas, School of Public Health, Center for Infectious Diseases; Department of Internal Medicine, St. Luke’s Episcopal Hospital; Department of Microbiology and Immunology, Baylor College of Medicine, Houston, TX, USA Véronique Erard, M.D. Médecin Adjointe, Infectiologie, HFR-Fribourg, Switzerland Scott E. Evans, M.D. Department of Pulmonary Medicine, The University of Texas M.D. Anderson Cancer Center, Houston, TX, USA Graeme N. Forrest, M.D. Division of Infectious Disease, Portland VA Medical Center, Portland, OR, USA Alison G. Freifeld, M.D. Department of Medicine, University of Nebraska Medical Center, Omaha, NE, USA Juan Gea-Banacloche, M.D. Experimental Transplantation and Immunology Branch, National Cancer Institute, Bethesda, MD, USA Michael Glickman, M.D. Department of Medicine, Infectious Disease Service, Memorial Sloan Kettering Cancer Center, New York, NY, USA Andre Goy, M.D. Hematology/Oncology, Internal Medicine, Hackensack University Medical Center, Hackensack, NJ, USA Bruno P. Granwehr, M.D. Department of Infectious Diseases, The University of Texas M.D. Anderson Cancer Center, Houston, TX, USA David E. Greenberg, M.D. Department of Infectious Diseases, National Institute of Allergy and Infectious Diseases, Bethesda, MD, USA Morgan Hakki, M.D. Division of Infectious Diseases, Oregon Health & Science University, Portland, OR, USA Stephen A. Harold Department of Medicine, The University of Texas, School of Public Health, Center for Infectious Diseases, Houston, TX, USA Sharone Hymes, M.D. Department of Dermatology, The University of Texas M.D. Anderson Cancer Center, Houston, TX, USA Mini Kamboj, M.D. Department of Medicine, Infectious Disease Service, Memorial Sloan-Kettering Cancer Center, New York, NY, USA Rana Kaplan, M.D. Department of Medicine, Pulmonary Medicine Service, Memorial Sloan–Kettering Cancer Center, New York, NY, USA

xvi

Adolf W. Karchmer, M.D. Division of Infectious Diseases, Beth Israel Deaconess Medical Center, Boston, MA, USA Dimitrios P. Kontoyiannis, M.D. Department of Infectious Diseases, Infection Control, and Employee Health, The University of Texas M.D. Anderson Cancer Center, Houston, TX, USA Konstantinos Leventakos, M.D. Department of Infectious Diseases, Infection Control, and Employee Health, The University of Texas M.D. Anderson Cancer Center, Houston, TX, USA Russell E. Lewis, Pharm. D. Department of Infectious Diseases, Infection Control, and Employee Health, The University of Texas M.D. Anderson Cancer Center, Houston, TX, USA Per Ljungman, M.D. Hematology Center, Karolinska University, Stockholm, Sweden Juan Carlos Lopez-Gutierrez, M.D. Department of Pediatric Surgery, Hospital Universitario Lu Paz, Universidad Autonoma de Madrid, Spain Rogelio López-Vélez, M.D. Tropical Medicine and Clinical Parasitology Unit, Department of Infectious Diseases, Ramón y Cajal Hospital, Instituto Ramón y Cajal de Investigación Sanitaria (IRYCIS), Madrid, Spain Bennett Lorber, M.D. Department of Medicine, Section of Infectious Diseases, Temple University School of Medicine, Philadelphia, PA, USA Johan A. Maertens, M.D., Ph.D. Department of Hematology, Acute Leukemia and Stem Cell Transplantation Unit, University Hospitals Leuven, Leuven, Belgium Dennis G. Maki, M.D. Department of Medicine, University of Wisconsin Hospital and Clinics, Madison, WI, USA Maurie Markman, M.D. Department of Gynecologic Oncology, The University of Texas M.D. Anderson Cancer Center, Houston, Texas, USA Kieren Marr, M.D. Division of Infectious Diseases, The Johns Hopkins Hospital, Baltimore, MD, USA Georg Maschmeyer, M.D. Department of Hematology, Oncology and Palliative Care, Klinikum Ernst von Bergmann, Potsdam, Germany Henry Masur, M.D. Critical Care Medicine Department, Clinical Center, National Institutes of Health, Bethesda, MD, USA Jayesh Mehta, M.D. Hematopoietic Stem Cell Transplant Program, Robert H. Lurie Comprehensive Cancer Center, Northwestern University Medical Center, Chicago, IL, USA Coralia N. Mihu, M.D. Department of Infectious Diseases, Infection Control, and Employee Health, The University of Texas M.D. Anderson Cancer Center, Houston, TX, USA

Contributors

Contributors

xvii

Malgorzata Mikulska, M.D. Division of Infectious Diseases, San Martino Hospital and University of Genoa, Genoa, Italy José G. Montoya, M.D. Department of Internal Medicine, Division of Infectious Diseases and Geographic Medicine, Stanford University School of Medicine, Stanford, CA, USA; Toxoplasma Serology Laboratory, Palo Alto Medical Foundation, Palo Alto, CA, USA Victor Mulanovich, M.D. Infectious Diseases Department, The University of Texas M.D. Anderson Cancer Center, Houston, TX, USA Daniel M. Musher, M.D. Departments of Medicine, Microbiology and Immunology, Baylor College of Medicine, Infectious Diseases Section, Veterans Affairs Medical Center, Houston, TX, USA Dionissios Neofytos, M.D. Division of Infectious Diseases, The Johns Hopkins Hospital, Baltimore, MD, USA Francesca F. Norman, M.D. Tropical Medicine and Clinical Parasitology Unit, Department of Infectious Diseases, Ramón y Cajal Hospital, Madrid, Spain Marcio Nucci, M.D. Department of Internal Medicine, Hematology Unit Head, Mycology Laboratory, Hospital Universitário Clementino Fraga Filho – Federal University of Rio de Janeiro, Rio de Janeiro, Brazil Susan O’Brien, M.D. Department of Leukemia, The University of Texas M.D. Anderson Cancer Center, Houston, TX, USA Genovefa Papanicolaou, M.D. Infectious Diseases Service, Memorial Sloan-Kettering Cancer Center, New York, NY, USA Alla Paskovaty, Pharm.D. Infectious Diseases Service, Memorial Sloan-Kettering Cancer Center, New York, NY, USA Ben de Pauw, M.D. Institute of Haematology and Clinical Oncology “Lorenzo e Ariosto Seràgnoli”, Sant’Orsola-Malpighi Hospital, University of Bologna, Bologna, Italy John R. Perfect, M.D. Department of Medicine, Division of Infectious Diseases and International Health, Duke University Medical Center, Durham, NC, USA David S. Perlin, Ph.D. Department of Clinical Sciences and Administration, College of Pharmacy, University of Houston, Texas Medical Center Campus, Houston, TX, USA; Department of Infectious Disease, Infection Control, and Employee Health, The University of Texas/M.D. Anderson Cancer Center, Houston, TX, USA Christopher D. Pfeiffer, M.D. Department of Medicine, Division of Infectious Diseases and International Health, Duke University Medical Center, Durham, NC, USA Issam Raad, M.D. Department of Infectious Diseases, Infection Control, and Employee Health, The University of Texas M.D. Anderson Cancer Center, Houston, TX, USA

xviii

Dhanesh B. Rathod, M.D. Department of Infectious Diseases, Infection Control, and Employee Health, The University of Texas M.D. Anderson Cancer Center, Houston, TX, USA Kenneth V. I. Rolston, M.D. Department of Infectious Diseases, Infection Control, and Employee Health, The University of Texas M.D. Anderson Cancer Center, Houston, TX, USA Amar Safdar, M.D. Department of Infectious Diseases, Infection Control, and Employee Health, The University of Texas M.D. Anderson Cancer Center, Houston, TX, USA Nasia Safdar, M.D. Section of Infectious Diseases, Department of Medicine, University of Wisconsin Medical School, Madison, WI, USA Hélène Schoemans, M.D. Department of Hematology, Acute Leukemia and Stem Cell Transplantation Unit, University Hospitals Leuven, Leuven, Belgium Brahm H. Segal, M.D. Department of Medicine and Immunology, Roswell Park Cancer Institute, Department of Medicine, School of Medicine and Biomedical Sciences, University of Buffalo, Elm & Carlton Streets, Buffalo, NY, USA Susan K. Seo, M.D. Infectious Diseases Service, Memorial Sloan-Kettering Cancer Center, New York, NY, USA Vickie R. Shannon, M.D. Department of Pulmonary Medicine, The University of Texas M.D. Anderson Cancer Center, Houston, TX, USA Samuel Shelburne, M.D. Department of Infectious Diseases, The University of Texas M.D. Anderson Cancer Center, Houston, TX, USA Marta Stanzani, M.D. Institute of Haematology and Clinical Oncology “Lorenzo e Ariosto Seràgnoli”, Sant’ Orsola-Malpighi Hospital, University of Bologna, Bologna, Italy David A. Stevens, M.D. Department of Medicine, Stanford University School of Medicine Division of Infectious Diseases, Santa Clara Valley Medical Center, Saratoga, CA, USA Diane E. Stover, M.D. Department of Medicine, Pulmonary Medicine Service, Memorial Sloan-Kettering, New York, NY, USA Aruna Subramanian, M.D. Division of Infectious Diseases, Johns Hopkins University School of Medicine, Baltimore, MD, USA Ursula Theuretzbacher, Ph.D. Center for Anti-Infective Agents, Vienna, Austria José Francisco Toma´s-Martinez, M.D. Department of Hematology, The University of Texas M.D. Anderson International España, Madrid, Spain

Contributors

Contributors

Harrys A. Torres, M.D. Department of Infectious Diseases, Infection Control, and Employee Health, The University of Texas M.D. Anderson Cancer Center, Houston, TX, USA Karen J. Vigil, M.D. University of Texas Health Science Center, Houston, TX, USA Claudio Viscoli, M.D. Division of Infectious Diseases, San Martino Hospital and University of Genoa, Genoa, Italy David M. Weinstock, M.D. Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, MA, USA John R. Wingard, M.D. Department of Medicine, University of Florida, Gainesville, FL, USA Markus Zeitlinger, M.D. Department of Clinical Pharmacology, Medical University of Vienna, Vienna, Austria

xix

Part I

Overview and Special Population

Chapter 1

Infections in Patients with Cancer: Overview Amar Safdar, Gerald Bodey, and Donald Armstrong

Abstractâ•… Patients with neoplastic disease are often highly susceptible to severe infections. The following factors influence the types, severity, and response to therapy of these infections: (1) Changing epidemiology of infections; (2) cancerand/or treatment-associated neutropenia; (3) acquired immune deficiency states such as cellular immune defect; (4) recent development of new-generation diagnostic tools including widely available DNA amplification tests; (5) effective intervention for infection prevention; (6) empiric or presumptive therapy during high-risk periods; (7) availability of new classes of highly active antimicrobial drugs; (8) strategies to promote hosts’ immune response; and (9) future measures. This introductory chapter intended for the reader to become familiar with the important historical milestones in the understanding and development in the field of infectious diseases in immunosuppressed patients with an underlying neoplasms and patients undergoing hematopoietic stem cell transÂ� plantation. Keywordsâ•… Cancer • Infection • Neutropenia • Immune defects • Diagnosis • Therapy Patients with neoplastic disease are often highly susceptible to severe infections. These are inclined to be difficult to prevent, diagnose, and treat. There are a variety of reasons for this which will be discussed in detail in the chapters of this book. We will introduce this volume by reviewing the history and background of such infections, where we believe major advances have been made and what we believe will be necessary to effectively prevent and manage such infections in the future. The following factors influence the types, severity, and response to therapy of these infections: (1) Changing epidemiology of infections; (2) cancer- and/or treatmentassociated neutropenia; (3) acquired immune deficiency states such as cellular immune defect; (4) recent Â�development A. Safdarâ•›(*) Department of Infectious Diseases, Infection Control, and Employee Health, The University of Texas M.D. Anderson Cancer Center, 1515 Holcombe Boulevard, Houston, TX 77030, USA e-mail: [email protected]

of new-generation diagnostic tools including widely Â�available DNA amplification tests; (5) effective intervention for infection prevention; (6) empiric or presumptive therapy during high-risk periods; (7) availability of new classes of highly active antimicrobial drugs; (8) strategies to promote hosts’ immune response; and (9) future measures.

Historical Perspective The introduction of chemotherapeutic regimens has expanded the population at risk, since many of these agents affect host defenses, most often causing neutropenia. However, even in acute leukemia, the malignancy with the highest frequency of infection, very little was published about infectious complications until the second half of the twentieth century. The paucity of published data is illustrated by a book on acute leukemia, published in 1958, which made no mention of infectious complications [1]. Indeed, at that time, some physicians attributed fevers in leukemia patients to a general hypermetabolic condition caused by the neoplasm. By the 1950s, several antineoplastic agents became available which caused at least transient improvement in some malignant diseases. Nitrogen mustard caused responses in Hodgkin disease, aminopterin caused responses in acute leukemia, and methotrexate cured choriocarcinoma in women. The subsequent use of multiple drug combinations in acute lymphocytic leukemia and Hodgkin disease represented major advances [2]. Another important advance was the use of platelet transfusions to control and prevent hemorrhage in acute leukemia patients with thrombocytopenia [3]. In an autopsy study, the frequency of hemorrhage as a cause of death in acute leukemia patients decreased from 67 to 37% due to the use of platelet transfusions [4]. Unfortunately, infection remained a major cause of death. There have been many reviews of the subjects over the years, some with international contributors and continuity which are references here [5–11].

A. Safdar (ed.), Principles and Practice of Cancer Infectious Diseases, Current Clinical Oncology, DOI 10.1007/978-1-60761-644-3_1, © Springer Science+Business Media, LLC 2011

3

4

Epidemiological Factors Exposures to organisms in the distant as well as recent past should be considered in patients with neoplastic disease. Latent infections may be activated in the presence of waning immunity whether it be due to the disease itself or to the treatment. The classic example of this is reactivation of latent tuberculous in patients with treatment-induced helper T-cell dysfunction. Additional latent infections which may be activated, for example, are histoplasmosis, coccidiomycosis, disease caused by the Herpes group of viruses, toxoplasmosis, strongyloidiasis, and others. These demand consideration and many such as TB, herpes simplex, and strongyloidiasis can be effectively treated prophylactically. Recent travel or residence and hospitalization may expose patients to organisms which may incubate such as malaria after travel to an endemic area or colonization due to drug-resistant bacteria such as Klebsiella, Pseudomonas, and Stenotrophomonas species acquired during a previous hospitalization. Questions to investigate epidemiologic factors should include exposures at home along with work, habits, and hobbies. Also, a detailed history of recent and remote travel and recreational activities may provide clues for an otherwise improbable diagnosis. All of these can be a source of infection, some of which can be avoided with appropriate patient education.

Hosts’ Susceptibility It is not surprising that the frequency of infection is related to the type of underlying malignancy and most infections occur in patients who are failing to respond to their cancer therapy. Surveys in the 1960s found that about 80% of patients with acute leukemia, 75% with lymphoma, but less than 40% of patients with metastatic carcinoma developed infection [12, 13]. There are a wide variety of factors that may impact on the susceptibility of cancer patients to infection [11]. Local factors such as tumor masses that may obstruct the bronchial tree or urinary tract and necrotic tumors in the gastrointestinal tract can result in infection. In an autopsy study of children with metastatic carcinoma, 80% of cases of pneumonia were associated with pulmonary metastases, aspiration, or tracheostomy [14]. Antibiotic therapy is often of limited efficacy in these types of tumors, unless the local predisposing factor can be removed.

Immunological Factors Neutropenia is the most important predisposing factor and can be due to the disease or its therapy. While there were some reports of the role of neutropenia in infection, a detailed

A. Safdar et al.

analysis of 52 patients with acute leukemia was published in 1966 [15]. This study demonstrated that the risk of infection was related to the degree and duration of neutropenia. The risk increased when the neutrophil count was less than 1,000/ mm3, but increased substantially when it was below 500/ mm3. Also, the risk of developing infection increased the longer the duration of neutropenia. One hundred percent of episodes of severe neutropenia (1,000 neutrophils/mL, whereas 81% with normal roentgenograms had 10) nodular skin lesions that develop necrotic center; skin biopsy is diagnostic and should be performed promptly. Mortality remains high despite the availability of highly active triazole drugs against this organism [87]. Unresolved immune suppression continues to influence treatment response among cancer and hematopoietic stem cell transplant (HSCT) recipients with systemic fungal disease [88]. Various strategies including donor granulocyte transfusions in patients with severe neutropenia have not shown significant improvement in outcomes in recent clinical trials [89]. Combined therapy using effective antifungal agents plus recombinant cytokines to boost macrophage, helper, and cytotoxic lymphocyte functions have been explored; a nonrandomized study using granulocyte-macrophage colony-stimulating

10

factor (GM-CSF) and interferon gamma (IFNg) which were safe and appeared to have a favorable impact in patients receiving donor granulocyte transfusions [90]. Safety of IFNg has been a concern due to potential cytokine-induced graft compromise and/or GVHD in recipients of allogeneic HSCT; these concerns were not observed in our patients with life-threatening fungal infections [91], although larger, randomized studies are needed to explore this important issue further. Similarly, drugs that may promote pathogen-directed immune capture by introducing configurational changes in these pathogens are being explored [92, 93].

Viral Infections For many years, little attention was focused on viral infections in cancer patients due to the lack of rapid diagnostic tests and effective therapy. For example, only in recent years have community respiratory viral infections been recognized as potentially serious to immunocompromised patients. Table  1.1 lists most of these viral infections and available therapy. Many acute viral infections represent reactivation of long-standing latent infection. Human herpes viruses are among the most common causes of viral infections in cancer patients and are associated with significant morbidity and mortality in severely immunocompromised hosts. Herpes simplex viruses cause oropharyngeal and esophageal disease and may disseminate to other organs. Reactivation of varicella-zoster virus occurs mainly in patients with leukemia and lymphoma and can result in localized infection (shingles), disseminated cutaneous infection, pneumonia, encephalitis, hepatitis, or small bowel disease [94]. CMV infection is most often due to reactivation of latent infection, but has also been attributed to transmission by white blood cell transfusions [24, 95]. It is a special risk to HSCT recipients who may receive infected tissue. CMV may cause hepatitis, meninoencephalitis, pneumonitis, or gastroenteritis [96, 97]. The disease has immunosuppressive effects that increase the risk of other infection. Prophylaxis or preemptive therapeutic strategies are necessary for patients undergoing stem cell transplantation [98]. Epstein–Barr virus can cause a fulminant fatal lymphoproliferative disorder in occasional patients following allogeneic stem cell transplantation. Immunocompromised cancer patients occasionally develop interstitial pneumonitis, encephalitis, or hepatitis due to human herpes virus 6 infections. Progressive multifocal leukoencephalopathy is a demyelinating disease of the brain caused by the JC virus which occurs infrequently among patients with CLL and Hodgkin disease. The disease is due to reactivation of latent infection that is prevalent in normal adults. Symptoms include visual disturbances, speech defects, and mental deterioration

A. Safdar et al.

l­eading to dementia and coma with 80% of patients dying within one year. Parvovirus B19 may cause anemia in cancer patients which may be followed by severe polyarthritis. Most patients have been infected with polyomavirus (BK) virus that persists in the genitourinary tract and is a major cause of hemorrhagic cystitis in HSCT recipients [99]. Community respiratory viral infections cause about 30% of respiratory infections in cancer patients during winter and spring and can be a serious threat to transplant recipients and patients with acute leukemia who may develop viral pneumonia or superinfection with bacteria or fungi [100, 101]. Epidemics have occurred in transplant and leukemia units. Some of these patients have very prolonged viral shedding after resolution of symptoms. Viruses causing infection include influenza A and B, respiratory syncytial virus (RSV), parainfluenza (PIV), and adenovirus. In stem cell transplant recipients following PIV and RSV infections, pulmonary obstructive defects were recently recognized; these may be severe and complete resolution may take longer than 12 months after the initial viral infection [102]. Novel respiratory viruses recently recognized to cause serious lifethreatening disease include human metapneumovirus, human cornonavirus NL63 and HKU1, agent of severe acute respiratory syndrome (SARS), and human bocavirus [103, 104]. Adenovirus also causes gastrointestinal infection, hepatitis, hemorrhagic cystitis, pancreatitis, and encephalitis; fatal disseminated adenovirus infections are seen in adults and pediatric patients with profound cellular immune defects such as cordblood transplant recipients with GVHD [105].

Parasitic Infections Neuro-hepatic toxoplasosis is more common in cancer and transplant recipients in the northeastern United States, whereas strongyloidiasis infestation rates are mostly seen in habitants of southeast and south-central US states. Similarly, amebiasis and giardiasis are infrequently seen in patients from rural residences who consume water from shallow contaminated wells. Latent Toxoplasma gondii infection is difficult to diagnose on the bases of travel, food consumption, or history of domestic feline exposure; serology may be diagnostic, although in patients with B-cell defects PCR analysis may be needed. Malaria is mostly seen in patients traveling to endemic regions without prophylaxis or receiving ineffective chemoprophylaxis due to drug-resistant strains of Plasmodium species. “Airport malaria” has also been seldom reported in patients who reside near airports with frequent international flights. Transfusion malaria has been observed in patients with neoplastic diseases and should be considered and explored in the presence of unexplained fever [106]. Chaga’s disease has also been transmitted by transfusions

1  Infections in Patients with Cancer: Overview

11

Table 1.1  Infections causing pneumonia in cancer patients based on the underlying immune defect Immune defect Bacteria Fungi Parasites Granulocytopenia

Staphylococcus aureus Streptococcus pneumoniae Streptococcus species Pseudomonas aeruginosa Enterobacteriaceae Escherichia coli

Cellular immune Dysfunction

Klebsiella species Stenotrophomonas maltophilia Acinetobacter species Nocardia asteroides complex Salmonella typhimurium spp. Salmonella enteritidis Rhodococcus equi Rhodococcus bronchialis Listeria monocytogenes Mycobacterium tuberculous Nontuberculous mycobacteria

Humoral immune Dysfunction Splenctomy

Mixed defects

Aspergillus and non-Aspergillus filamentous molds Pneumocystis jiroveci (P. carini) Cryptococcus neoformans

Viruses Herpes simplex virus I and II Varicella-zoster virus

Aspergillus fumigatus; and other Aspergillus spp. Non-Aspergillus hyalohyphomycosis Such as Pseudallescheria boydii, Fusarium solani. Mucorales (zygomycoses) Dematiaceous (black) fungi such as Alternaria Bipolaris, Curvularia, Scedosporium apiospermum Scedosporium prolificans

Toxoplasma gondii

Cytomegalovirus

Microsporidium spp. Leishmania donovani

Respiratory viruses Influenza A and Influenza B Parainfluenza type-3

Endemic mycoses due to Histoplasma Leishmania infantum capsulatum Coccidioides immitis, Blastomyces Strongyloides dermatitidis stercoralis Penicillium marnefie

Streptococcus pneumoniae Haemophilus influenzae Neisseria meningitidis Capnocytophaga canimorsus Campylobacter Streptococcus pneumoniae Staphylococcus aureus

Pneumocystis jiroveci (P. carini)?

Giardia lamblia Babesia microti

Pneumocystis jiroveci (P. carini) Aspergillus spp.

Toxoplasma gondii Strongyloides stercoralis

Haemophilus influenzae Klebsiella pneumonia

Candida spp. Cryptococcus neoformans

Pseudomonas aeruginosa Acinetobacter spp.

Mucorales (zygomycoses) Endemic mycoses (severe systemic dissemination)

Respiratory syncytial virus Adenovirus Varicella-zoster virus HHV 6 JC and BK virus Parvovirus B19 SARS-associated coronavirus? Paramyxovirus? Hantavirus? VZV Echovirus Enterovirus

Respiratory viruses Influenza Parainfluenza Respiratory syncytial virus Adenovirus VZV

Enterobacter spp. Stenotrophomonas maltophilia Nocardia asteroides complex Listeria monocytogenes Legionella spp. Patients with mixed immune defects include recipients of allogeneic hematopoietic stem cell transplant; acute or chronic graft versus host disease; myelodysplastic syndrome; adult T-cell leukemia lymphoma; antineoplastic agents like cyclophosphamide, fludarabine, and HHV6: Human herpesvirus 6 L. donovani and L. infantum may lead to serious visceral leishmaniasis. L. donovani is seen in Africa and Asia, L. infantum is seen in Africa, Europe, Mediterranean, and Central and South America. VZV is rarely associated with systemic dissemination in patients with humoral immune defects, or even those with mixed immune dysfunctions. Strongyloides stercoralis may lead to serious, life-threatening hyperinfection syndrome in patients with marked cellular immune defects

causing fevers and pericardial effusions [107]. This disease may become more common as the number of potential donors coming from endemic areas increases and also the

reduvid bug appears to be moving north into southwestern states. Screening donors may become necessary. A recent increase in fatal Babesia species infection reported since

12

November 2005 in the US has raised concerns of this rare intraerythrocytic parasite disease [108]. Hydated cyst due to Echinococcus granulosus and E. multilocularis and neurocycticercosis is difficult to distinguish from cystic brain tumor or bacterial or fungal brain abscess. Liver hydrated cyst may present as polymicrobial bacterial abscess in patients from the developing world.

End-Organ Infection Septicemia including disseminated infection and pneumonia are the most common sites of infection; urinary tract, skin, and central nervous system infection occurs less commonly. The site of infection is often related to the site of the primary tumor, a metastasis, or a surgical procedure. Septicemia is most likely to occur in patients with impaired host defenses. The frequency of infection has been determined in several autopsy studies.

Pneumonia The management of pneumonia in the cancer patient is often frustrating and difficult. The spectrum of potential pathogens is exceptionally broad including those that infect normal hosts and those that occur predominately in immunocompromised hosts; predisposing factors include deficiencies in host defense mechanisms such as neutropenia or hypo IgG, bronchial obstruction or ulceration due to tumor, mucosal damage due to chemotherapeutics agents, and the use of mechanical ventilation. Cancer patients may develop pulmonary infiltrates due to noninfectious causes such as hemorrhage, radiation pneumonitis, and leukoagglutinin reaction. Several neutropenia patients are unable to produce adequate inflammatory responses and thus may fail to produce persistent sputum, develop clinic signs and symptoms, or develop abnormalities on chest radiographs. In a study of gram-negative bacillary pneumonia in cancer patients (most of whom had hematological malignances), only 64% had abnormal radiographs at the onset of their pneumonia and 20% never developed abnormalities [109]. Identification of the infecting pathogen is often difficult. Adequate sputum specimens are often not available. The diagnostic yield from invasive procedures such as bronchoalveolar lavage is suboptimal. Biopsies are often contraindicated because of the risk of hemorrhage due to thrombocytopenia or coagulopathies. The use of CT scans and blood tests such as galactomannon detection for Aspergillosis have improved diagnostic capabilities [76].

A. Safdar et al.

Abdominal Infections A wide variety of infection agents may infect the gastrointestinal tract due to obstruction, ulceration, and other factors. This discussion will focus on two infections with potentially serious consequences in neutropenic patients: typhlitis and perianal infections. Typhlitis or neutropenic enterocolitis is characterized by well-demarcated ulcers, hemorrhage, and large masses of organisms with few inflammatory cells usually limited to the cecum, but can be more extensive. Computed tomography scans provide superior images of the intraabdominal organs and may be able to diagnose subclinical small bowel perforations, infected collections, and pneumatosis intestinalis, a serious complication which requires intense bowel management and presents as surgical dilemma [110]. Bacteremia occurs in 70% of patients. Therapy consists of broad-spectrum antibiotics, and anti-Candida agents, bowel rest, and decompression are important [110]. Perianal infections are most common in patients with acute monocytic leukemias. The prominent symptoms are fever and pain on defecation. Lesions often arise adjacent to a hemorrhoids and are indurated and ulcerated, often with extensive necroses. It is important to evaluate for recrudescent Herpes virus infections and perirectal abscess. Evaluation of surgical intervention may be obtained if there is not a prompt response to antimicrobial therapy or if a drainable focus is identified.

Catheter-Related Infections Most cancer patients receiving antineoplastic therapy have indwelling central venous access. Catheter infections are an important cause of delay in chemotherapy, hospitalization, cost of care, and deaths [111, 112]. Coagulase-negative Staphylococcus (CoNS) and other skin gram-positive bacteria are common pathogens. Catheter removal reduces risk of infection recurrences [113], and in patients with high-grade bacteremia or candidemia with or without hemodynamic compromise, the catheter should be removed immediately. A thorough evaluation for underlying endovascular infection such as septic thrombophlebitis may yield a source of persistent bacteremia, lack of complete response, and influence duration of systemic antimicrobial therapy. Factors that influence antimicrobial choice include (a) penetration of drug in the biofilm, (b) antimicrobial activity within the biofilm, and (c) activity against the nonplanktonic stationary phase of the microorganisms [114]. A detailed discussion of this important topic is presented in two chapters. This introductory chapter intended for the reader to become familiar with the important historical milestones in the understanding and development in the field of infectious

1  Infections in Patients with Cancer: Overview

diseases in immunosuppressed patients with an underlying neoplasm and patients undergoing hematopoietic stem cell transplantation.

References 1. Dameshek W, Gunz F. Leukemia. 1st ed. New York: Grune & Stratten; 1958. 2. DeVita VT, Chu E. A history of cancer chemotherapy. Cancer Res. 2008;68:8643–53. 3. Gaydos LA, Freireich EJ, Mantel N. The quantitative relation between platelet count and hemorrhage in patients with acute leukemia. N Engl J Med. 1962;266:905–9. 4. Hersh EM, Bodey GP, Nies BA, et  al. Causes of death in acute leukemia. A ten year study of 414 patients from 1954-1963. JAMA. 1965;193:105–9. 5. Armstrong D. Infections complicates of neoplastic diseases: diagnosis and management – part I. Clin Bull. 1976;6:135–41. 6. Armstrong D. Infections complicates of neoplastic diseases: diagnosis and management – part II. Clin Bull. 1977;7:13–20. 7. Armstrong D. Infections in patients with neoplastic disease. In: Verhoef J et  al., editors. Infections in the immunocompromised host – Pathogenesis, prevention and therapy. New York: Elsevier/ North Holland; 1980. p. 129–58. 8. Brown AE, Armstrong D, editors. Controversies in the management of infectious complications of neoplastic disease. New York: Yorke Medical Books; 1985. p. 1–424. 9. Armstrong D, Brown AE. Controversies in the management of infectious complications of neoplastic disease. Rev Infect Dis. 1993;17 Suppl 2:317–551. 10. Brown AE. White MH. Controversies in the management of immunocompromised patients. Clin Infect Dis. 1993;17 Suppl 2:317–551. 11. Safdar A, Armstrong D. Infectious morbidity in critically ill patients with cancer. Crit Care Clin. 2001;17:531–70. 12. Boggs DR, Frei III E. Clinical studies of fever and infection in cancer. Cancer. 1960;6:1240–53. 13. Raab SO, Hoeprich PD, Wintrob MM, et al. The clinical significance of fever in acute leukemia. Blood. 1960;16:1609–28. 14. Bodey GP, Hersh EM. The problem of infection in children with malignant disease. In: Neoplasia in childhood. Proceedings of the 12th Annual Clinical Conference at the University of Texas M. D. Anderson Hospital and Tumor Institute at Houston. Chicago, IL, Year Book Medical; 1969. p. 135–54. 15. Bodey GP, Buckley M, Sathe YS, et al. Quantitative relationship between circulating leukocytes and infection in patients with acute leukemia. Ann Intern Med. 1966;64:328–40. 16. Sickles EA, Greene WH, Wiernik PH. Clinical presentation of infection in granulocytopenic patients. Arch Intern Med. 1975;135:715–9. 17. Bodey GP, Powell Jr RD, Hersh EM, et al. Pulmonary complications of acute leukemia. Cancer. 1966;19:781–93. 18. Valdivieso M, Gil-Extremera B, Zornoza J, et al. Gram-negative bacillary pneumonia in the compromised host. Medicine. 1977;56:241–54. 19. Lawson RD, Gentry LO, Bodey GP, et al. Randomized study of tobramycin plus ticarcillin, tobramycin plus cephalothin and ticarcillin, or tobramycin plus mezlocillin in the treatment of infection in neutropenic patients with malignancies. Am J Med Sci. 1984;287:16–23. 20. Morse EE, Freireich EJ, Carbone PP, et al. The transfusion of leukocytes from donors with chronic myelogenous leukemia to patients with leukopenia. Transfusion. 1966;6:183–92.

13 21. Hester JP, Kellogg RM, Mulzet AP, et  al. Principles of blood separation and component extraction in a disposable continuousflow single-state channel. Blood. 1979;54:254–68. 22. Vallejos C, McCredie KB, Bodey GP, et al. White blood cell transfusions for control of infections in neutropenic patients. Transfusion. 1975;15:28–33. 23. Wright DG, Robichaud KJ, Pizzo PA, et  al. Lethal pulmonary reactions associated with the combined use of amphotericin B and leukocyte transfusions. N Engl J Med. 1981;304:1185–9. 24. Winston DJ, Ho WG, Young LS, et al. Prophylactic granulocyte transfusions during human bone marrow transplantation. Am J Med. 1980;68:893–7. 25. Bishton M, Chopra R. The role of granulocyte transfusions in neurtropenic patients. Br J Haematol. 2004;127:501–8. 26. Anderlini P, Champlin RE. Biologic and molecular effects of granulocyte colony-stimulating factor in healthy individuals: recent findings and current challenges. Blood. 2008;111: 1767–72. 27. Bodey GP, Hart JS, Freireich EJ, Frei III E. Studies of a patient isolator unit and prophylactic antibiotics in cancer chemotherapy. Cancer. 1968;22:1018–26. 28. Bodey GP, Rosenbaum B. Effect of prophylactic measures on the microbial flora of patients in protected environment units. Medicine. 1974;53:209–28. 29. Bodey GP, Rodriguez V. Infections in cancer patients on a protected environment - prophylactic antibiotic program. Am J Med. 1975;59:497–504. 30. Bodey GP, Gehan EA, Freireich EJ, Frei III E. Protected environment-prophylactic antibiotic program in the chemotherapy of acute leukemia. Am J Med Sci. 1971;252:138–51. 31. Bodey GP. Laminar air flow unit for patients undergoing cancer chemotherapy. In: Mirand EA, Back N, editors. Germ-Free Biology. New York, NY: Plenum Press; l969. p. 19–26. 32. Bodey GP, Rodriguez V, Murphy WK, Burgess MA, Benjamin RS. Protected environment-prophylactic antibiotic program for malignant sarcomas: Randomized trial during remission induction chemotherapy. Cancer. 1981;47:2422–9. 33. Bodey GP. Epidemiological studies of Pseudomonas speices in patients with leukmeia. Am J Med Sci. 1970;260:82–6. 34. Schimpff SC, Young VM, Greene WH, et al. Origin of infection in acute nonlymphocytic leukemia. Significance of hospital acquisition of potential pathogens. Ann Intern Med. 1972;77:707–14. 35. Hughes WT, Kuhn S, Chaudhary S, et al. Successful chemoprophylaxis for Pneumocystis carinii pneumonitis. N Engl J Med. 1977;297:1419–26. 36. Minamoto GY, Gold JWM, Scheinberg DA, et al. Infection with human T-cell leukemia virus type 1 in patients with leukemia. N Engl J Med. 1988;318:219–22. 37. Whitecar Jr JP, Bodey GP, Luna M. Pseudomonas bacteremia in cancer patients. Am J Med Sci. 1970;260:216–23. 38. Schimpff SC, Greene WH, Young VM, et  al. Significance of Pseudomonas aeruginosa in the patient with leukemia or lymphoma. J Infect Dis. 1974;130(Suppl):24–31. 39. Tapper ML, Armstrong D. Bactermeia due to Pseudomonas aeruginosa complicating neoplastic disease. A progress report. J Infect Dis. 1974;130 Suppl:14–23. 40. Bodey GP, Whitecar Jr JP, Middleman E, et al. Carbenicillin therapy of Pseudomonas infections. JAMA. 1971;218:62–6. 41. Middleman EA, Watanabe A, Kaizer H, Bodey GP. Antibiotic combinations for infections in neutropenic patients. Evaluation of carbenicillin plus either cephalothin or kanamycin. Cancer. 1972;30:573–9. 42. Aisenberg G, Rolston KV, Dickey BF, Kontoyiannis DP, Raad II, Safdar A. Stenotrophomonas maltophilia pneumonia in cancer patients without traditional risk factors for infection, 1997–2004. Eur J Clin Microbiol Infect Dis. 2007;26:13–20.

14 43. Safdar A, Rolston KV. Stenotrophomonas maltophilia: changing spectrum of a serious bacterial pathogen in patients with cancer. Clin Infect Dis. 2007;45:1602–9. 44. Sidjabat HE, Silveira FP, Potoski BA, et al. Interspecies spread of Klebsiella pneumoniae carbapenemase gene in a single patient. Clin Infect Dis. 2009;49:1736–8. 45. Louria DB, Hensle T, Armstrong D, et al. Listeriosis complicating malignant disease: a new association. Ann Intern Med. 1967;67: 261–81. 46. Safdar A, Armstrong D. Listeriosis in patients at a comprehensive cancer center, 1955–1997. Clin Infect Dis. 2003;37:359–64. 47. Armstrong D, Kiehn T, Boone N, et al. Mycobacterium haemophilum infections – New York City metropolitan area, 1990–1991. MMWR Morb Mortal Wkly Rep. 1991;40:636–43. 48. Kaplan MH, Armstrong D, Rosen P. Tuberculosis complicating neoplastic disease. A review of 201 cases. Cancer. 1974;33: 850–8. 49. Bodey GP, Middleman E, Umsawasdi T, et al. Infections in cancer patients – results with gentamicin sulfate therapy. Cancer. 1972;29:1697–701. 50. Klasterskly J, Vamecq G, Cappel R, et al. Effects of the combination of gentamicin and carbenicillin on the bactericidal activity of serum. J Infect Dis. 1972;125:183–6. 51. Hughes WT, Armstrong D, Bodey GP, et  al. From the working committee, Infectious Diseases Society of America: guidelines for the use of antimicrobial agents in neutropenic patients with unexplained fever. J Infect Dis. 1990;161:381–96. 52. Viscoli C, for the European Organization for the Research and Treatment of Cancer. Management of infection in cancer patients: studies of the EORTC International Antimicrobial Therapy Group (IATG). Eur J Cancer. 2002;38:82–7. 53. Pizzo PA, Armstrong D, Bodey G, et  al. From the Immunocompromised Host Society: the design, analysis, and reporting of the clinical trials on the empirical antibiotic management of the neutropenic patient. Report of a consensus panel. J Infect Dis. 1990;161:397–401. 54. De La Rosa GR, Jacobson KL, Rolston KV, Raad II, Kontoyiannis DP, Safdar A. Mycobacterium tuberculosis at a comprehensive cancer centre: active disease in patients with underlying malignancy during 1990-2000. Clin Microbiol Infect. 2004;10:749–52. 55. Aisenberg GM, Jacobson K, Chemaly RF, Rolston KV, Raad II, Safdar A. Extrapulmonary tuberculosis active infection misdiagnosed as cancer: Mycobacterium tuberculosis disease in patients at a Comprehensive Cancer Center (2001–2005). Cancer. 2005;104: 2882–7. 56. Han XY, Tarrand JJ, Infante R, Jacobson KL, Truong M. Clinical significance and epidemiologic analyses of Mycobacterium avium and Mycobacterium intracellulare among patients without AIDS. J Clin Microbiol. 2005;43:4407–12. 57. Safdar A, White DA, Stover D, Armstrong D, Murray HW. Profound interferon gamma deficiency in patients with chronic pulmonary nontuberculous mycobacteriosis. Am J Med. 2002; 113:756–9. 58. Safdar A, Armstrong D, Murray HW. A novel defect in interferongamma secretion in patients with refractory nontuberculous pulmonary mycobacteriosis. Ann Intern Med. 2003;138:521. 59. Rolston KV, Jones PG, Fainstein V, Bodey GP. Pulmonary disease caused by rapidly growing mycobacteria in patients with cancer. Chest. 1985;87:503–6. 60. Jacobson K, Garcia R, Libshitz H, Whimbey E, Rolston K, AbiSaid D, et  al. Clinical and radiological features of pulmonary disease caused by rapidly growing mycobacteria in cancer patients. Eur J Clin Microbiol Infect Dis. 1998;17:615–21. 61. Han XY, Dé I, Jacobson KL. Rapidly growing mycobacteria: clinical and microbiologic studies of 115 cases. Am J Clin Pathol. 2007;128:612–21.

A. Safdar et al. 62. Ingram CW, Tanner DC, Durack DT, Kernodle Jr GW, Corey GR. Disseminated infection with rapidly growing mycobacteria. Clin Infect Dis. 1993;16:463–71. 63. Bodey GP. Fungal infections complicating acute leukemia. J Chronic Dis. 1966;19:667–87. 64. Roden MM, Zaoutis TE, Buchanan WL, et al. Epidemiology and outcome of zygomycosis: a review of 929 reported cases. Clin Infect Dis. 2005;41:634–53. 65. Kontoyiannis DP, Lionakis MS, Lewis RE, et al. Zygomycosis in a tertiary-care cancer center in the era of Aspergillus-active antifungal therapy: a case-control observational study of 27 recent cases. J Infect Dis. 2005;191:1350–60. 66. Singer C, Kaplan MH, Armstrong D. Bacteremia and fungemia complicating neoplastic disease. A study of 364 cases. Am J Med. 1977;62:731–42. 67. Whimbey E, Kiehn TE, Brannon P, Blevins A, Armstrong D. Bacteremia and fungemia in patients with neoplastic disease. Am J Med. 1987;82:723–30. 68. Safdar A, Perlin DS, Armstrong D. Hematogenous infections due to Candida parapsilosis: changing trends in fungemic patients at a comprehensive cancer center during the last four decades. Diagn Microbiol Infect Dis. 2002;44:11–6. 69. Bodey GP, Luna M. Skin lesions associated with disseminated candidiasis. JAMA. 1974;229:1466–8. 70. Bodey GP, DeJongh D, Isassi A, Freireich EJ. Hypersplenism due to disseminated candidiasis in a patient with acute leukemia. Cancer. 1969;26:417–20. 71. Ferreira RP, Yu B, Niki Y, Armstrong D. Detection of Candida antigenuria in disseminated candidiasis by immunoblotting. J Clin Microbiol. 1990;28:1075–8. 72. Horn R, Wong B, Kiehn TE, Armstrong D. Fungemia in a cancer hospital: changing frequency, earlier onset, and results of therapy. Rev Infect Dis. 1985;7:646–55. 73. Wingard JR. The use of fluconazole prophylaxis in patients with chemotherapy-induced neutropenia. Leuk Lymphoma. 1992;8:353–9. 74. Wingard JR, Merz WG, Rinaldi MG, Johnson TR, Karp JE, Saral R. Increase in Candida krusei infection among patients with bone marrow transplantation and neutropenia treated prophylactically with fluconazole. N Engl J Med. 1991;325:1274–7. 75. Safdar A, van Rhee F, Henslee-Downey JP, Singhal S, Mehta J. Candida glabrata and Candida krusei fungemia after high-risk allogeneic marrow transplantation: no adverse effect of low-dose fluconazole prophylaxis on incidence and outcome. Bone Marrow Transplant. 2001;28:873–8. 76. Greene RE, Schlamm HT, Oestmann JW, et al. Imaging findings in acute invasive pulmonary aspergillosis: clinical significance of the halo sign. Clin Infect Dis. 2007;44:373–9. 77. Maschmeyer G, Beinert T, Buchheidt D, et al. Diagnosis and antimicrobial therapy of lung infiltrates in febrile neutropenic patients: Guidelines of the infectious diseases working party of the German Society of Haematology and Oncology. Eur J Cancer. 2009;45: 2462–72. 78. Marr KA, Boeckh M, Carter RA, Kim HW, Corey L. Combination antifungal therapy for invasive aspergillosis. Clin Infect Dis. 2004;39:797–802. 79. Fisher BD, Armstrong D. Cryptococcal interstitial pneumonia: value of antigen determination. N Engl J Med. 1977;97:1440–1. 80. White M, Cirrincione C, Blevins A, Armstrong D. Cryptococcal meningitis: outcome in patients with AIDS and patients with neoplastic disease. J Infect Dis. 1992;165:960–3. 81. Kontoyiannis DP, Wessel VC, Bodey GP, Rolston KVI. Zygomycosis in the 1990s in a tertiary-care cancer center. Clin Infect Dis. 2000;30:851–6. 82. Greenberg RN, Mullane K, van Burik JA, et al. Posaconazole as salvage therapy for zygomycosis. Antimicrob Agents Chemother. 2006;50:126–33.

1  Infections in Patients with Cancer: Overview 83. Walsh TJ, Melcher GP, Rinaldi MG, Lecciones J, McGough DA, Kelly P, et al. Trichosporon beigelii, an emerging pathogen resistant to amphotericin B. J Clin Microbiol. 1990;28:1616–22. 84. Asada N, Uryu H, Koseki M, Takeuchi M, Komatsu M, Matsue K. Successful treatment of breakthrough Trichosporon asahii fungemia with voriconazole in a patient with acute myeloid leukemia. Clin Infect Dis. 2006;43:e39–41. 85. Bayramoglu G, Sonmez M, Tosun I, Aydin K, Aydin F. Breakthrough Trichosporon asahii fungemia in neutropenic patient with acute leukemia while receiving caspofungin. Infection. 2008;36:68–70. 86. Rieger C, Geiger S, Herold T, Nickenig C, Ostermann H. Breakthrough infection of Trichosporon asahii during posaconazole treatment in a patient with acute myeloid leukaemia. Eur J Clin Microbiol Infect Dis. 2007;26:843–5. 87. Torres HA, Raad II, Kontoyiannis DP. Infections caused by Fusarium species. J Chemother. 2003;15 Suppl 2:28–35. 88. Safdar A. Strategies to enhance immune function in hematopoietic transplantation recipients who have fungal infections. Bone Marrow Transplant. 2006;38:327–37. 89. Seidel MG, Peters C, Wacker A, Northoff H, Moog R, Boehme A, et al. Randomized phase III study of granulocyte transfusions in neutropenic patients. Bone Marrow Transplant. 2008;42:679–84. 90. Safdar A, Rodriguez GH, Lichtiger B, Dickey BF, Kontoyiannis DP, Freireich EJ, et al. Recombinant interferon gamma1b immune enhancement in 20 patients with hematologic malignancies and systemic opportunistic infections treated with donor granulocyte transfusions. Cancer. 2006;106:2664–71. 91. Safdar A, Rodriguez G, Ohmagari N, Kontoyiannis DP, Rolston KV, Raad II, et al. The safety of interferon-gamma-1b therapy for invasive fungal infections after hematopoietic stem cell transplantation. Cancer. 2005;103:731–9. 92. Safdar A, Rodriguez G, Rolston KV, O'Brien S, Khouri IF, Shpall EJ, et al. High-dose caspofungin combination antifungal therapy in patients with hematologic malignancies and hematopoietic stem cell transplantation. Bone Marrow Transplant. 2007;39:157–64. 93. Safdar A. Fungal cytoskeleton dysfunction or immune activation triggered by beta-glucan synthase inhibitors: potential mechanisms for the prolonged antifungal activity of echinocandins. Cancer. 2009;115:2812–5. 94. Armstrong D, Chmel H, Singer C, Tapper M, Rosen PP. Nonbacterial infections associated with neoplastic disease. Eur J Cancer. 1975;11 Suppl:79–94. 95. Nichols WG, Price TH, Gooley T, Corey L, Boeckh M. Transfusiontransmitted cytomegalovirus infection after receipt of leukoreduced blood products. Blood. 2003;101:4195–200. 96. Meyers JD, Flournoy N, Thomas ED. Cytomegalovirus infection and specific cell-mediated immunity after marrow transplant. J Infect Dis. 1980;142:816–24. 97. Boeckh M, Leisenring W, Riddell SR, et al. Late cytomegalovirus disease and mortality in recipients of allogeneic hematopoietic stem cell transplants: importance of viral load and T-cell immunity. Blood. 2003;101:407–14. 98. Goodrich JM, Mori M, Gleaves CA, et  al. Early treatment with ganciclovir to prevent cytomegalovirus disease after allogeneic bone marrow transplantation. N Engl J Med. 1991;325:1601–7.

15 99. Arthur RR, Shah KV, Baust SJ, Santos GW, Saral R. Association of BK viruria with hemorrhagic cystitis in recipients of bone marrow transplants. N Engl J Med. 1986;315:230–4. 100. Kim YJ, Boeckh M, Englund JA. Community respiratory virus infections in immunocompromised patients: hematopoietic stem cell and solid organ transplant recipients, and individuals with human immunodeficiency virus infection. Semin Respir Crit Care Med. 2007;28:222–42. 101. Chemaly RF, Ghosh S, Bodey GP, Rohatgi N, Safdar A, Keating MJ, et al. Respiratory viral infections in adults with hematologic malignancies and human stem cell transplantation recipients: a retrospective study at a major cancer center. Medicine (Baltimore). 2006;85:278–87. 102. Erard V, Chien JW, Kim HW, Nichols WG, Flowers ME, Martin PJ, et al. Airflow decline after myeloablative allogeneic hematopoietic cell transplantation: the role of community respiratory viruses. J Infect Dis. 2006;193:1619–25. 103. Boeckh M. The challenge of respiratory virus infections in hematopoietic cell transplant recipients. Br J Haematol. 2008;143: 455–67. 104. Safdar A. Immune modulatory activity of ribavirin for serious human metapneumovirus disease: early i.v. therapy may improve outcomes in immunosuppressed SCT recipients. Bone Marrow Transplant. 2008;41:707–8. 105. La Rosa AM, Champlin RE, Mirza N, Gajewski J, Giralt S, Rolston KV, et al. Adenovirus infections in adult recipients of blood and marrow transplants. Clin Infect Dis. 2001;32:871–6. 106. Tapper ML, Armstrong D. Malaria complicating neoplastic disease. Arch Intern Med. 1976;136:807–10. 107. Grant IH, Gold JWM, Wittner M, et  al. Transfusion-associated acute Chagas disease acquired in the United States. Ann Intern Med. 1989;111:849–51. 108. Gubernot DM, Lucey CT, Lee KC, Conley GB, Holness LG, Wise RP. Babesia infection through blood transfusions: reports received by the US Food and Drug Administration, 1997–2007. Clin Infect Dis. 2009;48:25–30. 109. Chang HY, Rodriguez V, Narboni G, Bodey GP, Luna MA, Freireich EJ. Causes of death in adults with acute leukemia. Medicine. 1976;55:259–68. 110. Williams N, Scott AD. Neutropenic colitis: a continuing surgical challenge. Br J Surg. 1997;84:1200–5. 111. Howell PB, Walters PE, Donowitz GR, Farr BM. Risk factors for infection of adult patients with cancer who have tunneled central venous catheters. Cancer. 1995;75:1367–75. 112. Rotstein C, Brock L, Roberts RS. The incidence of first Hickman catheter-related infection and predictors of catheter removal in cancer patients. Infect Control Hosp Epidemiol. 1995;16:451–8. 113. Raad I, Kassar R, Ghannam D, Chaftari AM, Hachem R, Jiang Y. Management of the catheter in documented catheter-related coagulase-negative staphylococcal bacteremia: remove or retain? Clin Infect Dis. 2009;49:1187–94. 114. Fux CA, Wilson S, Stoodley P. Detachment characteristics and oxacillin resistance of Staphyloccocus aureus biofilm emboli in an in  vitro catheter infection model. J Bacteriol. 2004;186: 4486–91.

Chapter 2

Infections in Hematopoietic Stem Cell Transplant Recipients Georg Maschmeyer and Per Ljungman

Abstract  The risk of infection among allogeneic hematopoietic­ stem cell transplant (aHSCT) recipients is determined by patient age, underlying disease, the complications that occurred during preceding treatment regimens, the selected transplantation modality, and the severity of graft-versus-host disease. Immunological reconstitution after hematopoietic recovery has an impact on the type of posttransplant infectious complications, and infectionrelated mortality is significantly higher postengraftment than during the short posttransplant neutropenia. As different pathogenetic and epidemiological backgrounds of infections occur following aHSCT, three consecutive time periods posttransplant are separately described: the early posttransplant period (preengraftment, comprising 3 weeks), the intermediate posttransplant period (3 weeks to 3 months), and the late posttransplant period (later than day + 90). Keywords  Allogeneic • Hematopoietic stem cell transplant • Early infection • CMV • Late infections • Graft-versushost disease

Introduction Fever and Infection After Allogeneic Hematopoietic Stem Cell Transplant The risk of infection among allogeneic hematopoietic stem cell transplant (aHSCT) recipients is determined by patient age, underlying disease, the complications that occurred

G. Maschmeyer (*) Department of Hematology, Oncology and Palliative Care, Klinikum Ernst von Bergmann, Charlottenstrasse 72, 14467 Potsdam, Germany e-mail: [email protected]

during­ preceding treatment regimens, the selected transplantation­ modality, and the severity of graft-versushost disease (GvHD) [1, 2]. In comparison with patients undergoing high-dose chemotherapy and autologous stem cell transplantation, recipients of aHSCT are at a much higher risk of infection also after hematopoietic reconstitution, due to delayed recovery of T-cell and B-cell functions. Immunological reconstitution after hematopoietic recovery has an impact on the type of posttransplant infectious complications [3, 4], and infection-related mortality is significantly higher postengraftment than during the short posttransplant neutropenia. After nonmyeloablative conditioning, there is a lower risk of severe and fatal infections in the early posttransplant period [5–9]. Because of different pathogenetic and epidemiological backgrounds of infections, three consecutive time periods posttransplant are separately described: the early posttransplant period (preengraftment, comprising 3 weeks), the intermediate posttransplant period (3 weeks to 3 months), and the late posttransplant period (later than day + 90) (Fig. 2.1).

Early Posttransplant Period (Preengraftment; Earlier than Day +21) Epidemiology of Infections During Neutropenia Posttransplant Almost all patients receiving myeloablative conditioning regimens develop fever during neutropenia, and most of these febrile episodes are due to infections. The risk of severe bacterial or fungal infection in the early posttransplant period is markedly reduced when nonmyeloablative conditioning has been used. Clinical signs of infection apart from fever may be absent or discrete, and an infectious focus frequently will not be identified by clinical examination, microbiological, or imaging techniques. The differential diagnosis of noninfectious causes of fever, such as transfusion reactions,

A. Safdar (ed.), Principles and Practice of Cancer Infectious Diseases, Current Clinical Oncology, DOI 10.1007/978-1-60761-644-3_2, © Springer Science+Business Media, LLC 2011

17

18

G. Maschmeyer and P. Ljungman

Fig. 2.1  Infections following allogeneic hematopoietic stem cell transplantation (from Up to Date v18.3, Anaissie E, Marr KA, Thorner AR, 2010)

drug-related adverse events, allergy, and acute GvHD, must be considered. Infections in neutropenia after aHSCT may be life-­ threatening. Bacterial pathogens account for about 90% of infections during this phase. Epidemiological factors ­relevant for bacterial infections are shown in Table 2.1. Bacteremia, often related to central venous catheters (CVCs) and/or severe mucositis, occurs in up to 30% of patients after aHSCT, with the majority being caused by Gram-positive pathogens, predominantly coagulase-negative staphylococci, corynebacteria, and alpha-hemolytic streptococci [10–14]. Rarely, viridans streptococcal bacteremia may cause toxic shock and acute respiratory distress, potentially resulting in fatal outcome. Gram-negative infections are less frequent, but typically associated with higher morbidity and mortality. Gram-negative pathogens may enter the bloodstream via mucosal damage in the gastrointestinal tract of patients. Beyond that, fungal infection may occur in up to 15% of patients [15], and herpes simplex virus (HSV) infections emerge in this early posttransplant period unless acyclovir prophylaxis is given.

Table  2.1  Epidemiological aspects of bacterial infections after hematopoietic stem cell transplantation (HSCT) • Similar spectrum as neutropenic patients after intensive chemotherapy • Lower risk of severe and fatal infections early post-TxP after nonmyeloablative conditioning • Short neutropenia ± mucositis after autologous HSCT: infections comparable to other patients with short-term neutropenia, but Grampositive pathogens more frequent • Allogeneic HSCT: critical role of immune reconstitution −− Slow after T-cell depletion −− Slow after mismatched donor −− Slow/absent with significant graft-versus-host disease −− Chronic GvHD: functional asplenia

Diagnostic Procedures • Afebrile patient. −− Daily clinical exam + body temperature at least three times daily. Note:  antipyretic medication (steroids; analgesics such as metamizole).

2  Infections in Hematopoietic Stem Cell Transplant Recipients

•

•

•

•

•

•

•

•

•



−− Serum C-reactive protein (CRP) twice weekly. −− Aspergillus antigen (GM) ³twice weekly. First fever. −− Update physical exam, blood cultures, clinical chemistry, CRP, interleukin-6 (IL-6), and thoracic computed tomography (CT) scan; other measures according to clinical findings (see below). Persistent fever. −− Update physical exam, blood cultures, clinical chemistry, CRP, IL-6, and thoracic CT scan; consider abdominal ultrasound or magnetic resonance imaging (MRI). −− Check results of antigen testings. Fever + pulmonary infiltrates. −− Bronchoscopy + bronchoalveolar lavage (BAL) =>microscopy + culture for bacteria; test for Mycobacterium tuberculous (MTB), Pneumocystis, cytomegalovirus (CMV), respiratory viruses, adenovirus, Aspergillus + other fungi; check for Aspergillus GM; optional: Aspergillus-PCR and MTB-/Pneumocystis-PCR. Fever + signs of inflammation at CVC. −− Blood cultures from peripheral vein and from CVC. −− Follow-up cultures in case of cultures positive for Staphylococcus aureus and Candida spp. Fever accompanied by skin lesions. −− Blood cultures. −− Biopsy (=>histopathology and nonfixated =>microbiology). Neurological symptoms ± fever. −− Cerebrospinal fluid (CSF) =>human herpes virus-6 (HHV-6); Aspergillus GM; CMV; HSV, VZV. −− Fundoscopy. −− Cranial MRI. Fever + abdominal symptoms. −− Clostridium difficile toxins; noro-/rotaviruses; CMV; adenovirus; Epstein–Barr virus (EBV). Perianal infiltrate/abscess. −− Beware of results from inappropriate microbiological diagnostics suggesting monomicrobial etiology. Fever + increasing “liver function tests” =>viral (hepatitis B virus (HBV), varicella zoster virus (VZV); CMV, etc.), Candida? −− Liver ultrasound or CT or MRI (preferred) [16]. NB:  Pneumocystis jiroveci typically accompanied by lactate dehydrogenase rise

If causative microorganisms have been isolated from blood, urine, or CSF culture, follow-up cultures should be obtained to document microbiological eradication, whenever possible. Since conventional chest radiography is insensitive and has a low negative predictive value for detecting pulmonary infiltrates in neutropenic patients, multislice or high-resolution CT of the lungs should be obtained early in neutropenic patients and particularly in those not responding to initial

19 Table  2.2  Pulmonary infections and noninfectious complications following allogeneic HSCT Early 90 days) Infectious (pneumonia) Noninfectious

Bacterial, fungal, viral, protozoal pathogens Pulmonary edema Idiopathic pneumonia syndrome Diffuse alveolar hemorrhage Engraftment syndrome Delayed pulmonary toxicity syndrome Secondary pulmonary alveolar proteinosis, pulmonary veno-occlusive disease

Bacterial, fungal, viral pathogens Restrictive lung disease Constrictive bronchiolitis Lymphocytic interstitial pneumonitis

antimicrobial therapy [17]. Differential diagnoses to pulmonary infiltrates posttransplant are shown in Table 2.2.

Antimicrobial Therapy in Patients with Neutropenic Fever After Allogeneic Stem Cell Transplantation Fever of more than 38.2°C, or fever of 38.0°C lasting for an hour or longer, or that recurs within 24 h should give reason for immediate broad-spectrum antibacterial treatment. Microbiological identification of an underlying pathogen is achievable in about one third of all patients. Therefore, it has become an accepted clinical practice to initiate broad-spectrum antimicrobial treatment empirically, or preemptively in the presence of specific clinical or radiological signs or symptoms. For selection of empiric antibacterial therapy in patients with febrile neutropenia, local antimicrobial resistance pattern must be taken into account. Initial empirical regimens should be active against enterobacteriaceae, Pseudomonas aeruginosa, S. aureus, and streptococci. Clinical trials that investigated single-agent regimens in patients with neutropenic fever included only few patients after allogeneic stem cell transplantation. Patients with severe mucositis should not be given single-agent ceftazidime because of the risk of bacteremia due to viridans streptococci, whereas piperacillin-tazobactam, imipenem, or meropenem appear appropriate. In the case of skin infections or venous catheter infections, prompt addition of a glycopeptide antibiotic to the initial empiric regimen should be considered. Stopping the administration of glycopeptides should be considered, if no multiresistant Gram-positive bacteria have been identified. In febrile neutropenic patients with pulmonary infiltrates, prompt preemptive addition of a systemic antifungal active against Aspergillus spp. is recommended [16].

20

Second-Line Empiric Antimicrobial Regimens in Patients with Neutropenic Fever After Allogeneic Stem Cell Transplantation If a causative infectious agent has been identified, modification of the empirically started antibacterial therapy according to the in vitro susceptibility pattern should be considered. In case of clinical nonresponse after 72–96 h of full-dose antibacterial treatment, modification of the antimicrobial regimen must be discussed and diagnostic procedures be repeated. Particularly in patients given a prednisone equivalent at a dose of >2  mg/kg/day, broad-spectrum systemic antifungal treatment should be part of the second-line treatment.

G. Maschmeyer and P. Ljungman Table  2.3  Risk factors of invasive fungal infection in patients after allogeneic SCT Early fungal infection (45 years Intensive immunosuppression as part of the conditioning regimen • Immunosuppression as prophylaxis and/or treatment of GvHD Late fungal infection (>40 days after SCT) • Immunosuppression due to GvHD and its treatment (corticosteroid or other more intensive immunosuppressive treatments) • Transplants from unrelated donors or family donors mismatched for HLA class I and/or class II antigens • Cytomegalovirus infections and antiviral therapy • Age >45 years

Duration of Antimicrobial Treatment Antimicrobial treatment may be discontinued if all of the following conditions are met: defervescence for at least 48 h, negative cultures, no clinical or radiological evidence of an infection, and neutrophil recovery to above 1,000/mL. If infections have been microbiologically proven, it is advisable to repeat the initial diagnostic procedures, in order to document the microbiological response (e.g., blood cultures, CSF cultures, urine cultures, stool cultures, bronchial secretions in case of ventilated patients, smears). In some cases, narrowing the antimicrobial spectrum can be acceptable.

Early Fungal Infections After Allogeneic Stem Cell Transplantation Epidemiological aspects of invasive fungal infections in transplant patients are listed in Table 2.3. In this patient population, the incidence rate of systemic mycoses can be as high as 15%, or higher under certain circumstances [15]. Increased risk is expected in patients with a previous history of invasive fungal infection, long-lasting severe neutropenia, previous episodes of prolonged neutropenia, severe skin and mucosal damages due to conditioning treatment, transplantation outside of a laminar air flow unit, age >45 years, intensive immunosuppression as part of the conditioning regimen or for prophylaxis, and/or treatment of GvHD [18]. Apart from specific local epidemiological conditions, Candida and Aspergillus species are predominant pathogens. Fever unresponsive to broad-spectrum antibiotic treatment may be the only early symptom of a systemic fungal infection. In patients with pulmonary Aspergillus infection, pleuritic chest pain, cough, or hemoptysis may occur. Blood cultures may occasionally grow Candida species. Aspergillus

spp. detected in clinical specimens (such as saliva or throat swabs) from neutropenic patients are likely to indicate incipient invasive infection. At the same time, even if moulds have been isolated from BAL specimens, it may be difficult to distinguish between contamination and true invasive pulmonary infection, whereas in cases of documented invasive pulmonary aspergillosis, cultures from BAL are often negative. Serial screening of blood samples for Aspergillus galactomannan or beta-d-glucan as well as for fungal DNA by polymerase chain reaction (PCR) may be helpful for early initiation of broad-spectrum systemic antifungal treatment. Antifungal agents frequently used in this situation are liposomal amphotericin B and caspofungin, both being licensed for empirical treatment of refractory neutropenic fever. If, however, thoracic CT scan shows typical findings indicative of invasive aspergillosis, voriconazole might be the first choice, as in case of probable or proven aspergillosis. Antifungal treatment is continued at least until neutrophil recovery and resolution of clinical and radiological signs of infection. Other mould infections such as zygomycosis and fusariosis are rare, but increasingly reported in patients post-aHSCT, and in case of suspected zygomycosis, liposomal amphotericin B would be the preferred choice.

Early Viral Infections After Allogeneic Stem Cell Transplantation Virus infections can occur during the period before hematopoietic engraftment. HSV reactivates frequently in this early period unless acyclovir prophylaxis is given, and the clinical symptoms are frequently uncharacteristic [19]. Acyclovir-resistant viruses have been reported in different

2  Infections in Hematopoietic Stem Cell Transplant Recipients

patient series to occur in up to 10% and should be suspected if mucositis is prolonged in patients on acyclovir prophylaxis [20, 21]. Respiratory viral infections especially caused by RSV, parainfluenza, and influenza can occur early and are frequently due to nosocomial transmission within the transplant unit and therefore infection control procedures should be in place during times due to community outbreaks of these viruses [22–27]. Lower respiratory tract infection due to RSV and parainfluenza are associated with significant mortality. Patients, who are HBV DNA positive or HBsAg positive, before aHSCT are at risk for severe hepatitis and should be given prolonged antiviral prophylaxis [28–30].

Intermediate Posttransplant Period (3 Weeks to 3 Months) Specific Epidemiology of Infections in the Intermediate Posttransplant Period In the majority of allogeneic stem cell transplant recipients, infections emerge later than day +50 posttransplant. After hematopoietic reconstitution, a severe combined quantitative and functional deficiency in the T and B lymphocyte ­compartment persists. If T-cell depletion has been used, or if HLA-incompatibility between recipient and donor had to be accepted, immunodeficiency will be prolonged after ­transplantation. Immunodeficiency comprises impaired T helper cell function, immunoglobulin synthesis, and ­cytotoxic T cell response. Despite normalization of white blood cell counts, compromised granulocyte functions, primarily impairment of chemotaxis and phagocytosis, may persist.

Bacterial and Fungal Infections in the Intermediate Posttransplantation Period In 14% of patients, bacteremia occurs after hematopoietic engraftment, with a mortality rate comparable to that before and after engraftment. Among blood culture isolates, Grampositive pathogens (staphylococci in particular) are predominant, with the focus being identified in more than 50% of patients. Venous catheter infections are the cause for more than 30% of bacteremias, and fever and chills within the first hour after start of fluid infusion typically are indicating a catheter-related bacteremia. Other more frequent infections during the intermediate posttransplant period are pneumonias, preferably caused by Streptococcus pneumoniae, Klebsiella species, and P. aeruginosa, or by filamentous fungi such as Aspergillus. Among less frequent bacterial

21

pathogens relevant during this period are Listeria monocytogenes and Legionella pneumophila. While listeriosis may origin from products made from unpasteurized milk, the latter typically is related to the use of showers or jacuzzis after the water has been resting in the pipes for a longer period of time. In patients who are treated with tumor necrosis factor antagonists such as infliximab, a dramatic increase in the risk of invasive fungal infections must be considered [31, 32]. Apart from aspergillosis, some rare forms of invasive mycosis caused by Fusarium spp., zygomycetes, resistant Candida spp., Pseudallescheria boydii (or its asexual form, Scedosporium apiospermum), and others may occur during this time period [33]. Typically, patients with fusariosis have skin lesions and positive blood cultures, while zygomycetes cause clinical syndromes resembling aspergillosis.

Viral Infections Viruses are common causes of infections during the period from engraftment to day +90 after HSCT. The classic viral pathogen during this period is CMV called “the troll of transplantation.” CMV reactivates in 60–70% of pretransplant seropositive patients and primary infections occur in up to one third of seronegative patients with seropositive donors [34]. Established end-organ CMV disease is still associated with significant morbidity and mortality. Therefore, preventive strategies either by antiviral prophylaxis or preemptive therapy should be used [35, 36]. Antiviral prophylaxis has been less used, but new antiviral agents might make this strategy more attractive. Monitoring with sensitive assays such as pp65 antigenemia or quantitative PCR in blood is indicated in all aHSCT recipients to allow early initiation of antiviral therapy with ganciclovir or valganciclovir [35]. Epstein-Barr Virus (EBV) also reactivates very frequently after aHSCT, but rarely causes end-organ disease [37]. However, EBV-driven posttransplant lymphoproliferative disease (PTLD) is a complication with high mortality unless treated [38–41]. This complication is more commonly seen in EBV seronegative patients receiving grafts from EBV seropositive donors and in patients having delayed immune reconstitution such as after a T-cell-depleted or HLA-mismatched stem cell transplantation. PTLD frequently causes unspecific symptoms frequently with fever and lymphadenopathy and is associated with high levels of EBV in blood [39, 40, 42–44]. Rituximab (anti CD20 antibody) given either as preemptive therapy or as therapy for established PTLD is most likely effective, although no controlled trial has been performed [45–49]. Adenovirus infections can cause multiorgan disease including pneumonia, encephalitis, hepatitis, gastroenteritis, and hemorrhagic cystitis. Severe adenovirus disease is more ­frequently seen in children especially after transplant

22

procedures­resulting in delayed reconstitution of the immune ­system such as haploidentical transplants or mismatched cord blood grafts and monitoring for adenovirus in blood might be indicated in such patients [50–57]. Cidofovir is a potentially effective antiviral agent, but is associated with nephrotoxicity [58–60]. Other viral pathogens potentially important during this period after HSCT are HHV-6 associated with encephalitis and bone marrow suppression [61–66], BK-virus infections associated with hemorrhagic cystitis [67, 68], and respiratory viruses.

Late Period After Allogeneic Stem Cell Transplantation (Later than Day +90) Specific Epidemiology of Infections During the Late Posttransplant Period In the late posttransplant period, immune reconstitution usually advances, particularly in patients who have received a transplant from an HLA-identical family donor. These patients often show full hematopoietic reconstitution and early immune reconstitution. If no relevant GVHD emerges, prophylactic immunosuppression will typically be discontinued. Patients with a CD4-count of >200/mL blood and normalized serum immunoglobulin levels can be considered as immunocompetent without an increased risk of opportunistic infections. However, in the case of chronic GvHD, which may occur in more than 30% of patients, a severe combined cellular and humoral immunodeficiency will persist for a prolonged period of time. Mucosal damage, functional deficiencies of granulocytes (especially impaired chemotaxis), functional asplenia, and qualitative as well as quantitative T- and B-cell deficiencies pave the way to a significantly increased susceptibility to infections in these patients. In particular, bacterial infections of the respiratory tract constitute a major cause of death [69]. Life-threatening infections are typically caused by encapsulated bacteria such as S. pneumoniae or Haemophilus influenzae. Sinusitis, otitis media, and pharyngitis may indicate such infections in the late posttransplant period. Patients among this risk group presenting with signs of infection should receive immediate antibacterial treatment. An important pathogen of interstitial pneumonia in the late phase after allogeneic stem cell transplantation is P. jiroveci [70]. Without specific prophylaxis, about 30% of patients with chronic GvHD develop Pneumocystis pneumonia, which can take a fatal course in up to 15% of patients and prophylaxis given for at least 6 months (and longer in patients with chronic GvHD) is recommended to all patients. In regions

G. Maschmeyer and P. Ljungman

with relatively high prevalence rates, mycobacterial ­infections should be taken into consideration as well [71, 72].

Late Viral Infections After Stem Cell Transplantation Late-occurring CMV infection and disease have become more frequent during the last decade. These are associated with delayed and incomplete reconstitution of specific immunity, primarily of T-cells, and occur more commonly in patients experiencing severe GvHD [73, 74]. Prolonged monitoring and repeated antiviral therapy are needed in such patients, although toxicity from antiviral therapy and development of resistant CMV strains are important considerations [34, 36]. The possibility to reconstitute specific immunity by adoptive transfer of T-cells has been explored by several groups. VZV is an important pathogen after HSCT. Primary varicella – chickenpox – occurring in seronegative patients is an important complication especially in children. Preventive measures should be taken after exposure and i.v. acyclovir therapy given if the infection develops. VZV can reactivate also early after aHSCT, but infections are more commonly seen during the late posttransplant period. The clinical manifestations vary from localized herpes zoster – shingles – to visceral disseminated disease associated with high mortality [75–77]. Visceral disease including CNS disease can occur without cutaneous manifestations and can therefore be difficult to diagnose. Early initiation of antiviral therapy with intravenous acyclovir is ­crucial when visceral or disseminated VZV disease is suspected. Localized shingles can often be treated with orally given valacyclovir or famciclovir [37]. In many centers, longterm prophylaxis given for at least one year after HSCT is used to prevent VZV reactivations [78, 79]. Respiratory viruses, especially influenza, can also be severe late after HSCT. Yearly vaccination against influenza is therefore recommended [80]. RSV and parainfluenza infections have been associated with late respiratory compromise presumably through immune-mediated mechanisms [81, 82]. HBV infection can reactivate in previously HBV-infected patients, especially during prolonged treatment for GvHD. Reactivation can result in a potentially severe acute hepatitis and patients should be carefully monitored, and if signs of HBV reactivation develop, be given antiviral therapy [28–30].

Late Fungal Infections After Stem Cell Transplant Fungal infections during late transplant period are discussed in detail in Part III.

2  Infections in Hematopoietic Stem Cell Transplant Recipients

References 1. Walter E, Bowden RA. Infection in the bone marrow transplant recipient. Infect Dis Clin North Am. 1995;9:823–47. 2. Krüger WH, Bohlius J, Cornely OA, et al. Antimicrobial prophylaxis in allogeneic bone marrow transplantation. Guidelines of the infectious diseases working party (AGIHO) of the German Society of Haematology and Oncology. Ann Oncol. 2005;16:1381–90. 3. Tomblyn M, Chiller T, Einsele H, et al. Guidelines for preventing infectious complications among hematopoietic cell transplantation recipients: a global perspective. Biol Blood Marrow Transplant. 2009;15:1143–238. 4. Welniak LA, Blazar BR, Murphy WJ. Immunobiology of allogeneic­ hematopoietic stem cell transplantation. Annu Rev Immunol. 2007;25:139–70. 5. Aschan J. Risk assessment in haematopoietic stem cell transplantation: conditioning. Best Pract Res Clin Haematol. 2007;20:295–310. 6. Bachanova V, Brunstein CG, Burns LJ, et al. Fewer infections and lower infection-related mortality following non-myeloablative versus myeloablative conditioning for allotransplantation of patients with lymphoma. Bone Marrow Transplant. 2009;43:237–44. 7. Baron F, Storb R. Hematopoietic cell transplantation after reducedintensity conditioning for older adults with acute myeloid leukemia in complete remission. Curr Opin Hematol. 2007;14:145–51. 8. Junghanss C, Marr KA, Carter RA, et al. Incidence and outcome of bacterial and fungal infections following nonmyeloablative compared with myeloablative allogeneic hematopoietic stem cell transplantation: a matched control study. Biol Blood Marrow Transplant. 2002;8:512–20. 9. Meijer E, Dekker AW, Lokhorst HM, Petersen EJ, Nieuwenhuis HK, Verdonck LF. Low incidence of infectious complications after nonmyeloablative compared with myeloablative allogeneic stem cell transplantation. Transpl Infect Dis. 2004;6:171–8. 10. Blijlevens NM, Donnelly JP, de Pauw BE. Prospective evaluation of gut mucosal barrier injury following various myeloablative regimens for haematopoietic stem cell transplant. Bone Marrow Transplant. 2005;35:707–11. 11. Collin BA, Leather HL, Wingard JR, Ramphal R. Evolution, incidence, and susceptibility of bacterial bloodstream isolates from 519 bone marrow transplant patients. Clin Infect Dis. 2001;33:947–53. 12. Kolbe K, Domkin D, Derigs HG, Bhakdi S, Huber C, Aulitzky WE. Infectious complications during neutropenia subsequent to peripheral blood stem cell transplantation. Bone Marrow Transplant. 1997;19:143–7. 13. Krüger W, Rüssmann B, Kröger N, et al. Early infections in patients undergoing bone marrow or blood stem cell transplantation – a 7 year single centre investigation of 409 cases. Bone Marrow Transplant. 1999;23:589–97. 14. Yuen KY, Woo PCY, Hui CH, et al. Unique risk factors for bacteraemia in allogeneic bone marrow transplant recipients before and after engraftment. Bone Marrow Transplant. 1998;21:1137–43. 15. Marr KA, Carter RA, Boeckh M, Martin P, Corey L. Invasive aspergillosis in allogeneic stem cell transplant recipients: changes in epidemiology and risk factors. Blood. 2002;100:4358–66. 16. Einsele H, Bertz H, Beyer J, et  al. Infectious complications after allogeneic stem cell transplantation - Epidemiology and interventional therapy strategies. Ann Hematol. 2003;82 Suppl 2:S175–85. 17. Heussel CP, Kauczor HU, Heussel GE, et al. Pneumonia in febrile neutropenic patients and in bone marrow and blood stem-cell transplant recipients: use of high-resolution computed tomography. J Clin Oncol. 1999;17:796–805. 18. Barnes PD, Marr KA. Risks, diagnosis and outcomes of invasive fungal infections in haematopoietic stem cell transplant recipients. Br J Haematol. 2007;139:519–31.

23 19. Wade JC, Day LM, Crowley JJ, Meyers JD. Recurrent infection with herpes simplex virus after marrow transplantation: role of the specific immune response and acyclovir treatment. J Infect Dis. 1984;149:750–6. 20. Chakrabarti S, Pillay D, Ratcliffe D, Cane PA, Collingham KE, Milligan DW. Resistance to antiviral drugs in herpes simplex virus infections among allogeneic stem cell transplant recipients: risk factors and prognostic significance. J Infect Dis. 2000; 181:2055–8. 21. Chen Y, Scieux C, Garrait V, et al. Resistant herpes simplex virus type 1 infection: an emerging concern after allogeneic stem cell transplantation. Clin Infect Dis. 2000;31:927–35. 22. Harrington RD, Hooton TM, Hackman RC, et al. An outbreak of respiratory syncytial virus in a bone marrow transplant center. J Infect Dis. 1992;165:987–93. 23. Ljungman P, Ward KN, Crooks BN, et al. Respiratory virus infections after stem cell transplantation: a prospective study from the infectious diseases working party of the European group for blood and marrow transplantation. Bone Marrow Transplant. 2001;28:479–84. 24. McCann S, Byrne JL, Rovira M, et  al. Outbreaks of infectious diseases in stem cell transplant units: a silent cause of death for patients and transplant programmes. Bone Marrow Transplant. 2004;33:519–29. 25. Nichols WG, Corey L, Gooley T, Davis C, Boeckh M. Parainfluenza virus infections after hematopoietic stem cell transplantation: risk factors, response to antiviral therapy, and effect on transplant outcome. Blood. 2001;98:573–8. 26. Nichols WG, Guthrie KA, Corey L, Boeckh M. Influenza infections after hematopoietic stem cell transplantation: risk factors, mortality, and the effect of antiviral therapy. Clin Infect Dis. 2004; 39:1300–6. 27. Machado CM. Influenza infections after hematopoietic stem cell transplantation. Clin Infect Dis. 2005;41:273–4. 28. Locasciulli A, Bruno B, Alessandrino EP, et al. Hepatitis reactivation and liver failure in haemopoietic stem cell transplants for hepatitis B virus (HBV)/hepatitis C virus (HCV) positive recipients: a retrospective study by the Italian group for blood and marrow transplantation. Bone Marrow Transplant. 2003;31:295–300. 29. Kitano K, Kobayashi H, Hanamura M, et  al. Fulminant hepatitis after allogenic bone marrow transplantation caused by reactivation of hepatitis B virus with gene mutations in the core promotor region. Eur J Haematol. 2006;77:255–8. 30. Hsiao LT, Chiou TJ, Liu JH, et  al. Extended lamivudine therapy against hepatitis B virus infection in hematopoietic stem cell transplant recipients. Biol Blood Marrow Transplant. 2006;12:84–94. 31. Hamadani M, Hofmeister CC, Jansak B, et al. Addition of infliximab to standard acute graft-versus-host disease prophylaxis following allogeneic peripheral blood cell transplantation. Biol Blood Marrow Transplant. 2008;14:783–9. 32. Marty FM, Lee SJ, Fahey MM, et al. Infliximab use in patients with severe graft-versus-host disease and other emerging risk factors of nonCandida invasive fungal infections in allogeneic hematopoietic stem cell transplant recipients: a cohort study. Blood. 2003;102:2768–76. 33. Marr KA, Carter RA, Crippa F, Wald A, Corey L. Epidemiology and outcome of mould infections in hematopoietic stem cell transplant recipients. Clin Infect Dis. 2002;34:909–17. 34. Boeckh M, Ljungman P. How we treat cytomegalovirus in hematopoietic cell transplant recipients. Blood. 2009;113:5711–9. 35. Ljungman P, de la Camara R, Cordonnier C, et al. Management of CMV, HHV-6, HHV-7 and Kaposi-sarcoma herpesvirus (HHV-8) infections in patients with hematological malignancies and after SCT. Bone Marrow Transplant. 2008;42:227–40. 36. Zaia J, Baden L, Boeckh MJ, et al. Viral disease prevention after hematopoietic cell transplantation. Bone Marrow Transplant. 2009; 44:471–82.

24 37. Styczynski J, Reusser P, Einsele H, et  al. Management of HSV, VZV and EBV infections in patients with hematological malignancies and after SCT: guidelines from the second European conference on infections in Leukemia. Bone Marrow Transplant. 2009; 43:757–70. 38. Micallef IN, Chanabhai M, Gascoyne RD, et al. Lymphoproliferative disorders following allogeneic bone marrow transplantation: the Vancouver experience. Bone Marrow Transplant. 1998;22:981–7. 39. Juvonen E, Aalto SM, Tarkkanen J, et al. High incidence of PTLD after non-T-cell-depleted allogeneic haematopoietic stem cell transplantation as a consequence of intensive immunosuppressive treatment. Bone Marrow Transplant. 2003;32:97–102. 40. Sundin M, Le Blanc K, Ringden O, et  al. The role of HLA mismatch, splenectomy and recipient Epstein–Barr virus seronegativity as risk factors in post-transplant lymphoproliferative disorder following allogeneic hematopoietic stem cell transplantation. Haematologica. 2006;91:1059–67. 41. Landgren O, Gilbert ES, Rizzo JD, et al. Risk factors for lymphoproliferative disorders after allogeneic hematopoietic cell transplantation. Blood. 2009;113:4992–5001. 42. Gartner BC, Schafer H, Marggraff K, et  al. Evaluation of use of Epstein–Barr viral load in patients after allogeneic stem cell transplantation to diagnose and monitor posttransplant lymphoproliferative disease. J Clin Microbiol. 2002;40:351–8. 43. Greenfield HM, Gharib MI, Turner AJ, et al. The impact of monitoring Epstein–Barr virus PCR in paediatric bone marrow transplant patients: can it successfully predict outcome and guide intervention? Pediatr Blood Cancer. 2006;47:200–5. 44. Kinch A, Oberg G, Arvidson J, Falk KI, Linde A, Pauksens K. Posttransplant lymphoproliferative disease and other Epstein–Barr virus diseases in allogeneic haematopoietic stem cell transplantation after introduction of monitoring of viral load by polymerase chain reaction. Scand J Infect Dis. 2007;39:235–44. 45. Van Esser JW, Niesters HG, van der Holt B, et  al. Prevention of Epstein–Barr virus-lymphoproliferative disease by molecular monitoring and preemptive rituximab in high-risk patients after allogeneic stem cell transplantation. Blood. 2002;99:4364–9. 46. Wagner HJ, Cheng YC, Huls MH, et al. Prompt versus preemptive intervention for EBV lymphoproliferative disease. Blood. 2004;103:3979–81. 47. Weinstock DM, Ambrossi GG, Brennan C, Kiehn TE, Jakubowski A. Preemptive diagnosis and treatment of Epstein–Barr virus-associated post transplant lymphoproliferative disorder after hematopoietic stem cell transplant: an approach in development. Bone Marrow Transplant. 2006;37:539–46. 48. Styczynski J, Einsele H, Gil L, Ljungman P. Outcome of treatment of Epstein–Barr virus-related post-transplant lymphoproliferative disorder in hematopoietic stem cell recipients: a comprehensive review of reported cases. Transpl Infect Dis. 2009;11:383–92. 49. Omar H, Hagglund H, Gustafsson-Jernberg A, et al. Targeted monitoring of patients at high risk of post-transplant lymphoproliferative disease by quantitative Epstein–Barr virus polymerase chain reaction. Transpl Infect Dis. 2009;11:393–9. 50. Shields AF, Hackman RC, Fife KH, Corey L, Meyers JD. Adenovirus infections in patients undergoing bone-marrow transplantation. N Engl J Med. 1985;312:529–33. 51. Flomenberg P, Babbitt J, Drobyski WR, et al. Increasing incidence of adenovirus disease in bone marrow transplant recipients. J Infect Dis. 1994;169:775–81. 52. Chakrabarti S, Mautner V, Osman H, et al. Adenovirus infections following allogeneic stem cell transplantation: incidence and outcome in relation to graft manipulation, immunosuppression, and immune recovery. Blood. 2002;100:1619–27. 53. Lion T, Baumgartinger R, Watzinger F, et al. Molecular monitoring of adenovirus in peripheral blood after allogeneic bone marrow

G. Maschmeyer and P. Ljungman transplantation permits early diagnosis of disseminated disease. Blood. 2003;102:1114–20. 54. Van Tol MJ, Kroes AC, Schinkel J, et al. Adenovirus infection in paediatric stem cell transplant recipients: increased risk in young children with a delayed immune recovery. Bone Marrow Transplant. 2005;36:39–50. 55. Feuchtinger T, Lang P, Handgretinger R. Adenovirus infection after allogeneic stem cell transplantation. Leuk Lymphoma. 2007;48:244–55. 56. Robin M, Marque-Juillet S, Scieux C, et al. Disseminated adenovirus infections after allogeneic hematopoietic stem cell transplantation: incidence, risk factors and outcome. Haematologica. 2007;92:1254–7. 57. Symeonidis N, Jakubowski A, Pierre-Louis S, Jaffe D, Pamer E, Sepkowitz K, et al. Invasive adenoviral infections in T-cell-depleted allogeneic hematopoietic stem cell transplantation: high mortality in the era of cidofovir. Transpl Infect Dis. 2007;9:108–13. 58. Ljungman P, Ribaud P, Eyrich M, et  al. Cidofovir for adenovirus infections after allogeneic hematopoietic stem cell transplantation: a survey by the infectious diseases working party of the European group for blood and marrow transplantation. Bone Marrow Transplant. 2003;31:481–6. 59. Yusuf U, Hale GA, Carr J, et al. Cidofovir for the treatment of adenoviral infection in pediatric hematopoietic stem cell transplant patients. Transplantation. 2006;81:1398–404. 60. Neofytos D, Ojha A, Mookerjee B, et al. Treatment of adenovirus disease in stem cell transplant recipients with cidofovir. Biol Blood Marrow Transplant. 2007;13:74–81. 61. Drobyski WR, Dunne WM, Burd EM, et al. Human herpesvirus-6 (HHV-6) infection in allogeneic bone marrow transplant recipients: evidence of a marrow-suppressive role for HHV-6 in vivo. J Infect Dis. 1993;167:735–9. 62. Carrigan DR, Knox KK. Human herpesvirus 6 (HHV-6) isolation from bone marrow: HHV-6-associated bone marrow suppression in bone marrow transplant patients. Blood. 1994;84:3307–10. 63. Wang FZ, Linde A, Hagglund H, Testa M, Locasciulli A, Ljungman P. Human herpesvirus 6 DNA in cerebrospinal fluid specimens from allogeneic bone marrow transplant patients: does it have clinical significance? Clin Infect Dis. 1999;28:562–8. 64. Zerr DM, Gooley TA, Yeung L, et al. Human herpesvirus 6 reactivation and encephalitis in allogeneic bone marrow transplant recipients. Clin Infect Dis. 2001;33:763–71. 65. Zerr DM, Gupta D, Huang ML, Carter R, Corey L. Effect of antivirals on human herpesvirus 6 replication in hematopoietic stem cell transplant recipients. Clin Infect Dis. 2002;34:309–17. 66. Zerr DM, Corey L, Kim HW, Huang ML, Nguy L, Boeckh M. Clinical outcomes of human herpesvirus 6 reactivation after hematopoietic stem cell transplantation. Clin Infect Dis. 2005;40:932–40. 67. Leung AY, Suen CK, Lie AK, Liang RH, Yuen KY, Kwong YL. Quantification of polyoma BK viruria in hemorrhagic cystitis complicating bone marrow transplantation. Blood. 2001;98:1971–8. 68. Erard V, Kim HW, Corey L, et al. BK DNA viral load in plasma: evidence for an association with hemorrhagic cystitis in allogeneic hematopoietic cell transplant recipients. Blood. 2005;106:1130–2. 69. Chen CS, Boeckh M, Seidel K, et al. Incidence, risk factors, and mortality from pneumonia developing late after hematopoietic stem cell transplantation. Bone Marrow Transplant. 2003;32:515–22. 70. De Castro N, Neuville S, Sarfati C, et al. Occurrence of Pneumocystis jiroveci pneumonia after allogeneic stem cell transplantation: a 6-year retrospective study. Bone Marrow Transplant. 2005;36:879–83. 71. Cordonnier C, Martino R, Trabasso P, et al. Mycobacterial infection: a difficult and late diagnosis in stem cell transplant recipients. Clin Infect Dis. 2004;38:1229–36. 72. Erdstein AA, Daas P, Bradstock KF, Robinson T, Hertzberg MS. Tuberculous in allogeneic stem cell transplant recipients: still a problem in the 21st century. Transpl Infect Dis. 2004;6:142–6.

2  Infections in Hematopoietic Stem Cell Transplant Recipients 73. Boeckh M, Leisenring W, Riddell SR, et al. Late cytomegalovirus disease and mortality in recipients of allogeneic hematopoietic stem cell transplants: importance of viral load and T-cell immunity. Blood. 2003;101:407–14. 74. Hakki M, Riddell SR, Storek J, et al. Immune reconstitution to cytomegalovirus after allogeneic hematopoietic stem cell transplantation: impact of host factors, drug therapy, and subclinical reactivation. Blood. 2003;102:3060–7. 75. Locksley RM, Flournoy N, Sullivan KM, Meyers JD. Infection with varicella-zoster virus after marrow transplantation. J Infect Dis. 1985;152:1172–81. 76. Steer CB, Szer J, Sasadeusz J, Matthews JP, Beresford JA, Grigg A. Varicella-zoster infection after allogeneic bone marrow transplantation: incidence, risk factors and prevention with low-dose aciclovir and ganciclovir. Bone Marrow Transplant. 2000;25:657–64. 77. Martino R, Rovira M, Carreras E, et al. Severe infections after allogeneic peripheral blood stem cell transplantation: a matched-pair comparison of unmanipulated and CD34+ cell-selected transplantation. Haematologica. 2001;86:1075–86.

25 78. Boeckh M, Kim HW, Flowers ME, Meyers JD, Bowden RA. Long-term acyclovir for prevention of varicella zoster virus ­disease after allogeneic hematopoietic cell transplantation – a ­randomized double-blind placebo-controlled study. Blood. 2006;107:1800–5. 79. Erard V, Guthrie KA, Varley C, et  al. One-year acyclovir ­prophylaxis for preventing varicella-zoster virus (VZV) disease following hematopoietic cell transplantation: no evidence of rebound VZV disease after drug discontinuation. Blood. 2007; 110:3071–7. 80. Ljungman P, Cordonnier C, Einsele H, Englund J, Machado CM, Storek J, et al. Vaccination of hematopoietic cell transplant recipients. Bone Marrow Transplant. 2009;44:521–6. 81. Erard V, Chien JW, Kim HW, et al. Airflow decline after myeloablative allogeneic hematopoietic cell transplantation: the role of community respiratory viruses. J Infect Dis. 2006;193:1619–25. 82. Avetisyan G, Mattsson J, Sparrelid E, Ljungman P. Respiratory syncytial virus infection in recipients of allogeneic stem-cell transplantation: a retrospective study of the incidence, clinical features, and outcome. Transplantation. 2009;88:1222–6.

Chapter 3

Infections in Patients with Hematologic Malignancies Genovefa Papanicolaou and Jayesh Mehta

Abstract  Hematologic malignancies are a heterogeneous group of diseases with differing clinical manifestations, disease course, response to therapy, and long-term outcome. More intensive therapies are also being extended to older age groups and to patients with significant comorbidities, which were traditionally excluded from such treatment. These intensive treatment approaches are associated with multiple complications; infections from a wide variety of pathogenic and opportunistic organisms being amongst the commonest and the most serious. Infections affect quality of life, delay potentially saving chemotherapy and pose a substantial burden for the health care system and remain an important cause of death. In this chapter we outline the common immune defects and associated infections frequently seen in patients with ­hematologic malignancies.

resulted in alterations in the types of infections seen. Hersh et al. noticed this trend almost half a century ago [6]. Over the study period, infections were amongst the major causes of death in 70% of the acute leukemia patients who died. Fatal staphylococcal infections declined by 85% over the period but fatal fungal infections tripled. Microbiologically or clinically documented infection develops in 60–80% of patients undergoing induction ­chemotherapy for acute leukemia. Up to 50% of patients with chronic lymphocytic leukemia suffer from recurrent infections. Infections affect quality of life, delay potentially saving chemotherapy, pose a substantial burden for the health care system and remain an ­important cause of death for patients with hematologic malignancies [7–14].

Keywords  Leukemia • Lymphoma • Multiple myeloma • Infections • Serious • Immune dysfunction • New chemotherapy • Old age

Immune Host-Defects in Hematologic Malignancies

Introduction Hematologic malignancies are a heterogeneous group of ­diseases with differing clinical manifestations, disease course, response to therapy, and long-term outcome. Response to therapy and long-term survival has improved significantly over the last few decades as a result of the ­development of more intensive and effective treatment approaches [1, 2]. These intensive treatment approaches are associated with multiple complications in patients with hematologic malignancies. Infections from a wide variety of pathogenic and opportunistic organisms are amongst the commonest and the most serious [2–5]. The availability of new, broad-spectrum antimicrobial agents has improved ­outcomes – but has also G. Papanicolaou (*) Infectious Diseases Service, Memorial Sloan-Kettering Cancer Center, New York, NY, USA e-mail: [email protected]

Under normal circumstances, the immune system consists of multiple layers that each contribute to protection against infection. Redundancy at the cellular and signaling level limits the potential for microbes to escape this defensive system, and modest compromise of one layer of immune defense may not be readily apparent. In patients with hematologic malignancies, the redundancy of the immune system has been severely compromised. Innate immune defenses like mucosal integrity, neutrophil and monocyte function, and numbers may be compromised as a result of cytotoxic therapy or steroids. In many cases, the underlying disease or therapy has compromised or even eliminated the adaptive immune system (i.e., antibody generation and T-cell responses). The underlying immune defect often plays a major role in defining the type and clinical presentation of many infections. For example, infection by Streptococcus pneumoniae often presents as fulminant sepsis in splenectomized patients [15, 16]. Community respiratory viruses causing self-limited upper respiratory infections in healthy individuals have been associated with high mortality in patients with leukemia [17]. Prevention of infection is

A. Safdar (ed.), Principles and Practice of Cancer Infectious Diseases, Current Clinical Oncology, DOI 10.1007/978-1-60761-644-3_3, © Springer Science+Business Media, LLC 2011

27

28

G. Papanicolaou and J. Mehta

Table 3.1  Infections control: close attention to all potential sources of infection [18] Environment • Ventilation and construction: Aspergillus • Water: Legionella pneumophila • Environmental surfaces: Clostridium difficile, VRE • Invasive medical devices Health care workers • Hand washing • Isolation technique • Preemptive barrier precautions Visitors Contact with food, flowers, toys

Table  3.2  Role of host defenses on patient response: neutropenia significantly worsened response rates in patients with invasive aspergillosis [19] Patient response to therapy Neutropenia status

Aspergillus fumigatus

Aspergillus terreus

P value

No neutropenia Neutropenia resolved Persistent neutropenia

53% (8/15) 50% (4/8) 10% (1/10)

50% (4/8) 44% (4/9) 6% (1/15)

0.01 0.01 0.01

p­ aramount for the most vulnerable patients. Close attention is paid to all potential sources of infection including the environment, health care workers, and visitors (Table 3.1) [18]. Immune recovery plays an important role on the outcome of infection (Table 3.2) [19–21]. A useful initial approach is the recognition of the major predisposing factors broadly classified as: (1) granulocytopenia and qualitative defects of phagocytes; (2) cellular immune dysfunction; (3) humoral immune dysfunction and (4) impaired mucosal integrity. More than one predisposing factors may be present at any given time. Classic ­associations between specific immune defects and types of infectious pathogens are helpful to guide the initial approach to the patient. Table  3.3 shows the predominant pathogens ­associated with major immune defects.

Neutropenia Neutrophils are the first line of defense against pyogenic bacteria and fungi. The lack of inflammatory response due to the absence of neutrophils may result in rapid progression of infection in the absence of signs and symptoms. The relationship of granulocytopenia and risk of infection is wellestablished. It is widely appreciated that risk of infection increases very little until the granulocyte count drops below 500/mm3 and rises rapidly as the count approaches 0 [22]. The severity and duration of neutropenia are important determinants of the type of infectious complications (Fig. 3.1).

Patients whose neutropenia persists for 10 days or longer are at high risk not only for acute bacterial infections, but also for secondary infections due to fungi and viruses. The risk of infection is more pronounced in patients who have a rapidly falling granulocyte count than in patients who have a prolonged stationary granulocyte count such a in myelodysplastic syndrome [23]. The bacterial pathogens isolated from neutropenic patients at the early stages of neutropenia tend to originate from the patients’ endogenous flora. Gram-negative enteric organisms, a-hemolytic streptococci and enterococci are associated with oral and gastrointestinal mucositis. Skin related pathogens (staphylococci, coagulase negative staphylococci, and Corynebacterium spp.) are associated with line infections (Table 3.3). The most common sites of infection are the bloodstream followed by lung and GI tract. Seeding of infection from the bloodstream may lead to localized abscesses that may become clinically apparent after neutrophil recovery (Fig.  3.2). Fever with mucositis and abdominal pain raises suspicion of neutropenic enterocolitis (typhlitis). Since the mid-1980s, 60–70% of bacteremias associated with a single organism are caused by Gram-positive organisms [24–26] (Fig.  3.3). An increase in Gram-positive and polymicrobial infections is noted over the 15-year period of study. The rise in the incidence of multiresistant organisms among patients with hematologic malignancies may reflect broader trends observed in nosocomial pathogens [27, 28]. The 30-day mortality rates for neutropenic patients with bacteremia approach 30% [13, 29, 30]. Polymicrobial bacteremia and fungemia have been associated with highest mortality rates [31]. Viridans streptococcal bacteremia has been associated with a toxic-shock-like syndrome with hypotension maculopapular rash palmar desquamation, and acute respiratory distress syndrome [32–34]. Persistent fever in a neutropenic patient despite broad spectrum antibiotics should raise suspicion for fungal infection. Prior to the implementation of preemptive antifungal therapy, up to 50% patients treated for leukemia were found to have a fungal infection at autopsy [35]. Empiric antifungal therapy has substantially reduced the incidence of fungal infections during neutropenia [36]. Only the minority of fungal infections is diagnosed antemortem (Fig. 3.4). The likelihood of patients requiring systemic antifungals during neutropenia has changed over the years due to changes in our use of antifungal prophylaxis (Table 3.4). The predominant fungal pathogens in neutropenic patients are shown on Table 3.3. Candida remains the most common yeast causing bloodstream infection (Fig.  3.5). In a recent study, the incidence of candidemia in patients with hematologic malignancies was approximately 20 episodes per 1,000

3  Infections in Patients with Hematologic Malignancies

29

Table 3.3  Predominant pathogen association with selected host immune defects Host defense Bacteria Fungi Neutropenia

Cellular dysfunction

Humoral dysfunction

Anatomic disruption   Upper GI

  Lower GI

  Skin

Splenectomy

Gram-positive Staphylococci (CoNS, S. aureus) Streptococci (a-hemolytic, Group D) Anaerobes Anaerobic streptococci Clostridium spp. Bacteroids spp. Legionella Salmonella

Candida spp. Aspergillus spp. Trichosporon spp. Fusarium spp. Mucor

Nocardia Mycobacteria (TB and atypical) Live bacteria vaccine (BCG) Gram positive S. pneumoniae S. aureus Gram-negative H. influenzae Neisseria spp. Enteric organisms

Coccidioides Candida spp. Pneumocystis

Mouth flora a-Hemolytic streptococci Anaerobic Peptostreptococci Gram-positive (Group D streptococci) Enteric Gram-negative organisms Anaerobes Bacteroides, Clostridium spp.,   Group D streptococci Gram-positive Staphylococci Corynebacterium spp. Gram-negative Pseudomonas spp. Enteric Gram-negative Mycobacteria M. abscesses fortuitum, Mycobacterium chelonei Gram-positive S. pneumoniae DF2 bacillus Capnocytophaga canimorsus Gram-negative H. influenzae Salmonella spp. Neisseria meningitidis

Candida

patient days despite antifungal prophylaxis. Non-albicans species predominated with Candida tropicalis and Candida parapsilosis accounting for 40% of all isolates. An increase in the frequency of fluconazole-resistant Candida species including Candida glabrata and Candida krusei has been noted in several studies possibly as a result of antifungal ­prophylaxis with fluconazole [37, 38]. A complication of

Cryptococcus Histoplasma

Viruses

Other

Herpes viruses VZV, CMV, HSV, HHV6, EBV Respiratory viruses Live virus vaccines

Toxoplasma Cryptosporidium

Enteroviruses Live vaccine viruses

Strongyloides

Giardia

Herpes simplex

Candida

Candida Aspergillus

Babesia

candidemia is chronic disseminated candidiasis (hepatosplenic candidiasis). The only symptom may be persistent fever after resolution of neutropenia. Numerous target lesions in the liver and spleen may be apparent by CT imaging [39] (Fig. 3.6). Infections by filamentous fungi, Aspergillus being the most common, are an important cause of mortality in patients

30

Fig. 3.1  Episodes of severe infection related to numbers of circulating neutrophils. Bodey et al. examined the occurrence of severe infection in 52 patients with acute leukemia treated at the National Institutes of Health from 1959 to 1963. The risk of developing severe infection at a given neutrophil count was calculated form the number of severe ­infections occurring per 1,000 days at each neutrophil count. When severe neutropenia was present 43 episodes of severe infection were observed per 1,000 days

G. Papanicolaou and J. Mehta

Fig.  3.3  Changing epidemiology of bacterial infections in patients with hematologic malignancies. An increase in Gram-positive and polymicrobial infections is noted over the 15-year period of study 315

209

BMT

85

Acute leukemia

56

BMT

Acute leukemia 39% 26%

6% Clinical data

6% Autopsy data

Fig. 3.4  The incidence of fungal infections is underestimated due to our inability to establish the diagnosis antemortem. Left: Number of patients dying after allogeneic bone marrow transplantation or induction/salvage therapy for acute leukemia (blue bars) over a 12-year period at the Royal Marsden Hospital, UK and percentage in whom fungal infections were clinically suspected (red bars). Right: Autopsy data: The subset of patients who had autopsy (blue bars) and percentage in whom fungus was detected (red bars)

Fig.  3.2  MRI of thigh of a patient with lymphoma after neutrophil recovery form intensive chemotherapy. Multiple abscesses are shown in proximal/mid left. Diffuse edema and enhancement is noted in the muscles, along the fascia and subcutaneous issues. Aspirate of the abscess grew Pseudomonas aeruginosa

with hematologic malignancies [3, 40, 41]. The lungs are the most common site of infection followed by the sinuses. Aspergillosis of the central nervous system (CNS) may result from hematogenous dissemination with mortalities approaching 100% (Fig. 3.7) [42]. Zygomycosis is much less common than aspergillosis, but a rising trend has been noted increased use of prolonged antifungal prophylaxis with agents active against ­Aspergillus, such as voriconazole (Fig. 3.8) [43, 44]. Other molds previously thought to be contaminants or colonizers have been recognized to be causing invasive

mycoses in severely immunosuppressed patients. Sinusitis with emerging fungal pathogens including Fusarium and dark-walled molds are being recognized with increasing frequency [45].

Qualitative Phagocyte Defects Chemotaxis, cell activation, phagocytosis, and intra- or extracellular killing by oxygen-dependent and ­oxygen-independent pathways may be compromised in the presence of adequate cell numbers. Intrinsic functional defects of granulocytes exist in patients with acute leukemia, myelodysplastic syndromes and preleukemic states [46]. From a clinical perspective such patients with borderline granulocyte count should be approached as if they had absolute neutropenia.

3  Infections in Patients with Hematologic Malignancies

31

Table 3.4  Changes in the incidence of presumed/confirmed fungal infection with changes in antifungal prophylaxis Royal Marsden Hospital, UK, 1992–1995

Stage of disease  A. Acute Myelogenous Leukemia Within 6 weeks of induction Autograft in CR1 Allograft in CR1 B. Multiple Myeloma Within 12 weeks of induction Early autograft Allograft for relapsed disease

Northwestern Memorial Hospital, Chicago, IL, 2002–2005

Antifungal prophylaxis

% of patients requiring systemic antifungal therapy

Antifungal prophylaxis

% of patient requiring systemic antifungal therapy

Nystatin Nystatin Nystatin

44% 31% 51%

Fluconazole Fluconazole Voriconoazole

13%   8% 15%

None Nystatin Nystatin

  4%   9% 67%

Fluconazole Fluconazole Voriconazole

  0%   0%   0%

Percentage of patients requiring systemic antifungals during treatment for acute myelogenous leukemia (A) or multiple myeloma (B) over a 12-year period (Courtesy of Dr. Jayesh Mehta)

Fig.  3.5  Incidence of candidemia among patients with hematologic malignancies during 2001–2007 at the M.D Anderson Cancer Center. A slight decrease in the incidence of candidemia was observed during the last 2 years of the study. Seventy-six percent of infections were caused by non-albicans species. The attributable during the study period was 19%

Leukemia and lymphoma are associated with intrinsic defects in monocyte function. Circulating monocytes are precursors for alveolar and lamina propria macrophages, the mucosal cells that play an important role in earliest defense against pulmonary and intestinal infection [47]. Although the exact relationship between circulating monocytes and infection has not been explored it is reasonable though to hypothesize that these cells would make an important ­contribution in the defense against bacterial or fungal infections. Treatment modalities such chemotherapy, corticosteroids, radiation or growth factors may result in phagocyte dysfunction. The major effect of corticosteroids on granulocyte function appears to be impairment of chemotaxis which decreases localized inflammatory response. In vitro, steroids inhibit

Fig.  3.6  Hepatosplenic candidiasis in a patient with acute myelogenous leukemia in remission. The patient developed persistent fever after four cycles of chemotherapy and associated prolonged neutropenia. CT of the abdomen: Multiple hypodense lesions in the liver. Liver biopsy showed granulomatous necrosis with yeast forms consistent with Candida

phagocytosis, microbicidal activity and antibody dependent cytotoxicity. In addition, a number of monocyte functions are impaired including chemotaxis, bactericidal activity, and production of interleukin-1 and TNF-a. Use of Corticosteroids predisposes to infections by pathogens that depend on ­phagocyte function such as Staphylococcus aureus, Enterobacteriaceae, and fungi. The risk of infection increases when the adult equivalent of prednisone 20–40  mg/day or higher is administered for longer than 4–6 weeks. Steroids may also enhance susceptibility to infection though delay in wound healing, increased skin fragility, and impairment of lymphocyte function.

32

G. Papanicolaou and J. Mehta

Fig. 3.7  Disseminated aspergillosis in a child with leukemia; Left: Chest CT demonstrating cavitary lesion. Biopsy showed septate hyphae. Right: MRI showing bilateral frontal lobe ring enhancing lesions

Fig. 3.8  Influenza and Mucor pneumonia in a heavily treated patient with lymphoma. Initially the patient presented with influenza infection and a left lung consolidation (a). Several weeks after empiric treatment with voriconazole the patient presented with respiratory distress and

diffuse interstitial infiltrates (b). Sputum culture grew Aspergillus spp. and Mucor spp. Nasopharyngeal cultures were persistently positive for influenza A. Autopsy showed broad nonseptate hyphae consistent with zygomycosis (c)

3  Infections in Patients with Hematologic Malignancies

Cellular Immune Dysfunction Intrinsic defect in cellular immunity is the hallmark of immune dysfunction seen in lymphoma. T-cell function is required for macrophage activation and subsequent micro­ bicidal activity. In the absence of functional T-cells, intracellular pathogens may survive and replicate inside macrophages. The pathogens causing infections in patients with impaired T-cell immunity include a broad array of intracellular bacteria, fungi, DNA viruses, and protozoa (Table 3.2). Endemic fungi like Histoplasma or Coccidioides, or parasites like Strongyloides stercoralis may reactivate and cause severe disease during intense chemotherapy. A variety of opportunistic pathogens like atypical mycobacteria, Nocardia (Fig. 3.9), or toxoplasma may cause disseminated disease in patients with impaired T-cell immunity. Lymphoreticular malignancy and corticosteroid therapy seem to be a major factor for infection by the opportunistic fungi Cryptococcus spp. and Pneumocystis jiroveci (Fig. 3.10). The most common manifestation of cryptococcal infection is meningitis though primary pneumonia, fungemia, and cutaneous or visceral dissemination may occur. Protective immunity against most viruses is highly dependent on virus-specific, MHC- restricted T-lymphocytes. Infections by the herpes viruses including herpes simplex (HSV), Varicella-zoster virus (VZV), and cytomegalovirus (CMV) are almost exclusively due to reactivation. HSV infections range from 15% among CLL patients treated with fludarabine to 90% of patients with acute leukemia. Mucocutaneous HSV disease will frequently present with an atypical appearance and can mimic other pathogens. The

Fig. 3.9  Pulmonary nocardiosis in patients with lymphoma treated with high dose steroids, CT Chest (right) showed consolidation with cavitation in the right middle lobe and left lower lobe (left). At autopsy ­bilateral

33

incidence of VZV infections ranges from 2% in patients with CML receiving imatinib to 10–15% in patients with CLL receiving fludarabine or alemtuzumab to 25% of patients with Hodgkin’s lymphoma. More than 80% of VZV infections present with localized disease. Patients who are VZV naïve are at risk for primary infection with either wild type or vaccine strains and should be counseled about the risk of developing such an infection. T-cell depleting agents (e.g., alemtuzumab) and aggressive chemotherapy (e.g., hyper-CVAD and acute leukemia induction) appear to increase the incidence of CMV infection and ­disease [48]. Fulminant hepatitis B may occur during immunosuppression in patients with active hepatitis B [49, 50]. Disseminated disease caused by vaccination with live viruses such as ­varicella and polio and or bacteria such as BCG have been reported [51].

Humoral Immune Dysfunction Multiple myeloma and chronic lymphocytic leukemia are ­associated with intrinsic defects in humoral immunity. Immunoglobulins and complement provide opsonic, lytic, and neutralizing activities essential for protection against bacterial pathogens. Impaired humoral immunity is a risk factor for recurrent infections from polysaccharide-encapsulated bacteria such as S. pneumoniae, Haemophilus influenzae, or Neisseria spp. Pyogenic infections by enteric Gram-negative organisms and staphylococci are also frequently encountered (Table 3.3).

pneumonia and pulmonary abscesses were noted (middle) with colonies of filamentous micro-organisms morphologically consistent with Nocardia species (right)

34

G. Papanicolaou and J. Mehta

underlying hematologic malignancy who present with fever should be managed initially as potentially septic.

Mucosal Impairment

Fig.  3.10  Patient with lymphoma treated with Alemtuzumab and ­steroids presenting with shortness of breath. CT of chest showed nodular and interstitial infiltrates. Septate hyphae consistent with Aspergillus and Pneumocystis were noted at autopsy

The sites of infection are most frequently the upper respiratory tract, the urinary tract, or the skin. Septicemia occurs less frequently, but it does cause significant morbidity and mortality. Normal humoral immune function is essential for the ­control of enteroviruses in the acute viremic phase. Chronic carriers of Hepatitis B are at risk for severe Hepatitis B reactivation after treatment with rituximab, a monoclonal antibody against B-cells [52]

Splenic Dysfunction The spleen removes opsonized and non-opsonized microorganisms form the circulation and is the principal organ for the production of antibody to polysaccharide antigens. Splenectomized patients have decreased levels of IgM and properdin, and may be deficient in other phagocytosis ­promoting peptides. Splenectomized patients are highly ­vulnerable to bacterial infections by S. pneumoniae and H. influenzae, as well as Neisseria spp. and Capnocytophaga canimorsus (Table 3.2). Overwhelming infection after splenectomy occurs in 6.9% of post splenectomy patients with 50% of the infection-related deaths occurring within the first 3 months post splenectomy. Even overwhelming infection may present with subtle symptoms. Asplenic patients with

Mucosal immunity of the gastrointestinal, sinopulmonary, and genitourinary tracts constitute the first line of host defense against invasion of these barriers by microorganisms. Oral and gastrointestinal mucositis is a frequent complication of treatment of patients with hematologic malignancies ranging from mild erythema and soreness to ulcerations with hemorrhage. The pathophysiology of mucositis is complex, involving initial damage by oxygen free radicals, followed by upregulation of proinflammatory cytokines and microvascular damage. This ultimately leads to ulceration, which is exacerbated by bacterial, viral, and fungal colonization [53–55]. In neutropenic patients, more than 80% of microbiologically documented infections are caused by organisms that are part of the endogenous flora and about one-half of the etiologic agents are acquired by the patients subsequent to hospital admission [56, 57].

Immune Defects in Specific Malignancies The recognition of the principal immune defect enables us to assess the relative risk for specific pathogens. The predominant immune defects associated with most common hematologic malignancies and their treatments are listed on Table 3.5. Multiple immune deficits can coexist in the same patient.

Acute Leukemia Severe and prolonged neutropenia and mucositis are the major immune defect in patients with acute leukemia undergoing intensive chemotherapy. Intensive induction chemotherapy or consolidation chemotherapy for acute leukemia are usually followed by 2–4 weeks or 8–12 days of neutropenia respectively. Fever develops in the vast majority of patients with neutropenia. An organism is identified in approximately 50% of the cases. The most common ­infections and causative agents during the neutropenic phase in acute leukemia are listed on Table 3.3. Patients with acute lymphoblastic leukemia, hairy cell leukemia, and mycoses fungoides have an intrinsic impairment in cellular immunity. These patients are susceptible to opportunistic pathogens like P. jiroveci and reactivation of

3  Infections in Patients with Hematologic Malignancies

35

Table 3.5  Predominant immune defects associated with common hematologic malignancies Host defense impairment Cellular Disease Neutropenia Phagocyte defects immunity AML

Disease +++ + Treatment +++ ALL Disease +++ + Treatment +++ Hairy cell leukemia Disease ++* + Treatment ++ CLL Disease ± + Treatment ++ CML Disease ± + Treatment ± Myeloma Disease ± + Treatment ± to ++ Lymphoma Disease − + Treatment ± to +++ MDS Disease ++ + Treatment ++ ++ to +++: Significant; +: known; ±: not prominent;* also monocytopenia

latent viruses primarily varicella zoster and herpes simplex (Table 3.5) [58].

Chronic Lymphocytic Leukemia In chronic lymphocytic leukemia, an intrinsic defect in the clonal B-cells leads to unbalanced immunoglobulin chain synthesis resulting in hypogammaglobulinemia. Impairments in cellular immunity, the complement system, and variable neutropenia depending on the extent of marrow involvement may also contribute to susceptibility to infections [59]. The incidence of infection correlates with the duration and the stage of disease as well as with the serum levels of immunoglobulins (particularly IgG). Up to 50% of patients with CLL experience recurrent infections [59]. The 25-year risk for severe infection was 26% in one cohort of 125 patients analyzed over 10 years [60]. In patients treated with conventional chemotherapy, infections are likely to be mainly bacterial; including S. pneumoniae, S. aureus, and enteric Gram-negative organisms. Opportunistic infections such as Pneumocystis and fungal infections are uncommon as cellular immunity is preserved in the early stages of disease [59]. Treatment with purine analogues (fludarabine and clofaradine) usually results in prolonged lymphopenia [59, 61]. Reactivation of HSV or VZV occurs approximately in 10–15% of patients treated with fludarabine [62–64]. The relative risk of infection related to cell-mediated immunity deficit is increased when fludarabine is combined with ­corticosteroids or alemtuzumab treatment [59, 61, 65]. The

− + + ++ ± + ± ++ − ± ± ++ +++ ++ − +

Humoral immunity

Splenic dysfunction

Anatomic disruption

− + – ++ ± ++ +++ ++ − − +++ ++ ± ++ ± −

− − − − − If splenectomy ± ++

± +++ ± +++ ± ± ± + ± ± ± ± to + ± ± to +++ ±

± If splenectomy

incidence of ­infection in patients treated with Alemtuzumab appears higher  in pretreated patients compared to patients receiving ­alemtuzumab as first line single agent [66–74]. Although the majority or infections occur within the first 3 months of treatment some infections were reported up to 180 days post treatment [75, 76]. The addition of the anti B-cell antibody rituximab to nucleoside analogue based therapy does not appear to increase the risk of early or late infections [77, 78].

Myeloma In multiple myeloma, the intrinsic immune deficits are a reduction in polyclonal immunoglobulin synthesis and a failure to make appropriate antibody responses post immunization. Cell-mediated immunity is intact unless patients are treated with corticosteroids of cytotoxic chemotherapy. The degree of humoral immunity impairment is related with the stage of disease [79]. Patients who have responded to chemotherapy and are in the “plateau phase” are at a low risk [80]. Infection is the most common cause of death among patients with multiple myeloma, accounting for 20–50% of all deaths. The sites of infections and causative pathogens are reviewed in Table 3.5. Most infections in newly ­diagnosed patients and during the first cycles of chemotherapy are caused by S. pneumoniae, S. aureus and H. influenzae, or Neisseria spp. In patients with renal failure, relapsed and/or refractory advanced disease, more than 90% of the infectious episodes are caused by Gram-negative bacilli or S. aureus [81]. Patients treated with bortezomib, particularly in

36

c­ ombination with dexamethasone or cytotoxic agents, have a high incidence of varicella-zoster infections and prophylaxis with acyclovir is indicated [82]. An increased incidence of Aspergillosis has been reported after intensive chemotherapy and associated neutropenia [83]. Strategies for the prevention of infection in patients with myeloma include prophylactic antibiotics, passive immunization with polyclonal or specific immunoglobulins, and vaccinations.

Lymphoma Impaired cellular immunity is the predominant intrinsic host immune defect in patients with Hodgkin’s disease and nonHodgkin’s lymphomas. In addition, cytotoxic agents ­administered alone or in combination with steroids are major causes of impaired T-cell immunity. Fludarabine or Alemtuzumab (MabCampath®) result in profound and prolonged depletion of lymphocytes. Radiation can result in impaired T-cell immunity especially when given in combination with other immunosuppressive agents. Some degree of cellular dysfunction may persist even in patients who have been in remission for several years [84]. The most common sites and pathogens associated with impaired cellular immunity are reviewed in Table 3.3. In patients with T-cell lymphoma, bacterial sepsis is the most common infectious complication and accounts for about 50% of all deaths [85, 86]. Cutaneous bacterial infections in particular due to S. aureus are the most common followed by cutaneous herpes simplex and VZV, bacteremia, bacterial pneumonia, and urinary tract infection [87]. In patients with T-cell lymphoma treated with alemtuzumab, CMV (CMV reactivation) is the most common viral infection followed by HSV and VZV [88, 89]. A high incidence of mold infections has also been reported [88]. Patients with HTLV-1 associated T-cell lymphoma are at increased risk of infection with S. stercoralis and possibly with Mycobacterium tuberculous and leprosy [90].

Summary Over the last two decades, the increasing intensity of chemotherapeutic regimens and improved survival of patients with hematologic malignancies have lead to an increased population of highly immunocompromised individuals. Our evolving understanding of the immune system, sensitive diagnostic methods, and effective antiinfectives have led to an overall improvement in the incidence of infections and associated mortality. The relentless selective pressures on pathogens

G. Papanicolaou and J. Mehta

have led to shifts in the epidemiology of infections. A multidisciplinary team consisting of oncologists, infectious ­disease clinicians, and basic scientists is required to address the constantly evolving challenges of infections in patients with hematologic malignancies.

References 1. Burnett AK. Acute myeloid leukemia: treatment of adults under 60 years. Rev Clin Exp Hematol. 2002;6(1):26–45; discussion 86–7. 2. Koistinen P et  al. Long-term outcome of intensive chemotherapy for adults with de  novo acute myeloid leukaemia (AML): the nationwide AML-92 study by the Finnish Leukaemia Group. Eur J Haematol. 2007;78(6):477–86. 3. Chamilos G et al. Invasive fungal infections in patients with hematologic malignancies in a tertiary care cancer center: an autopsy study over a 15-year period (1989–2003). Haematologica. 2006;91(7):986–9. 4. Elonen E et  al. Comparison between four and eight cycles of intensive chemotherapy in adult acute myeloid leukemia: a randomized trial of the Finnish Leukemia Group. Leukemia. 1998;12(7):1041–8. 5. Castaigne S et al. Randomized comparison of double induction and timed-sequential induction to a “3 + 7” induction in adults with AML: long-term analysis of the Acute Leukemia French Association (ALFA) 9000 study. Blood. 2004;104(8):2467–74. 6. Hersh EM et al. Causes of death in acute leukemia: a ten-year study of 414 patients from 1954–1963. JAMA. 1965;193:105–9. 7. Caggiano V et al. Incidence, cost, and mortality of neutropenia hospitalization associated with chemotherapy. Cancer. 2005;103(9): 1916–24. 8. Dale DC. The benefits of haematopoietic growth factors in the management of gynaecological oncology. Eur J Gynaecol Oncol. 2004;25(2):133–44. 9. Darmon M et al. Impact of neutropenia duration on short-term mortality in neutropenic critically ill cancer patients. Intensive Care Med. 2002;28(12):1775–80. 10. Kuderer NM et  al. Mortality, morbidity, and cost associated with febrile neutropenia in adult cancer patients. Cancer. 2006;106(10): 2258–66. 11. Talcott JA et al. Risk assessment in cancer patients with fever and neutropenia: a prospective, two-center validation of a prediction rule. J Clin Oncol. 1992;10(2):316–22. 12. Rossini F. Prognosis of infections in elderly patients with haematological diseases. Support Care Cancer. 1996;4(1):46–50. 13. Elting LS et al. Outcomes of bacteremia in patients with cancer and neutropenia: observations from two decades of epidemiological and clinical trials. Clin Infect Dis. 1997;25(2):247–59. 14. Malik I, Hussain M, Yousuf H. Clinical characteristics and therapeutic outcome of patients with febrile neutropenia who present in shock: need for better strategies. J Infect. 2001;42(2):120–5. 15. Styrt B. Infection associated with asplenia: risks, mechanisms, and prevention. Am J Med. 1990;88(5N):33N–42. 16. Norris RP, Vergis EN, Yu VL. Overwhelming postsplenectomy infection: a critical review of etiologic pathogens and management. Infect Med. 1996;13:779–83. 17. Torres HA et al. Characteristics and outcome of respiratory syncytial virus infection in patients with leukemia. Haematologica. 2007;92(9):1216–23. 18. Zuccotti G, Sepkowitz KA. Management of infection in oncology patients: infection control. In: Wingard JR, Bowden RA, editors. Infections in oncology patients. Philadelphia, PA: Martin Dunitz; 2003.

3  Infections in Patients with Hematologic Malignancies 19. Hachem RY et  al. Aspergillus terreus: an emerging amphotericin B-resistant opportunistic mold in patients with hematologic malignancies. Cancer. 2004;101(7):1594–600. 20. Uzun O et  al. Risk factors and predictors of outcome in patients with cancer and breakthrough candidemia. Clin Infect Dis. 2001;32(12):1713–7. 21. Anaissie EJ et al. Predictors of adverse outcome in cancer patients with candidemia. Am J Med. 1998;104(3):238–45. 22. Bodey GP et al. Quantitative relationships between circulating leukocytes and infection in patients with acute leukemia. Ann Intern Med. 1966;64(2):328–40. 23. Pizzo PA. Fever in immunocompromised patients. N Engl J Med. 1999;341(12):893–900. 24. Rolston KV et al. The spectrum of Gram-positive bloodstream infections in patients with hematologic malignancies, and the in  vitro activity of various quinolones against Gram-positive bacteria isolated from cancer patients. Int J Infect Dis. 2006;10(3):223–30. 25. Safdar A et al. Changing trends in etiology of bacteremia in patients with cancer. Eur J Clin Microbiol Infect Dis. 2006;25(8):522–6. 26. Donowitz GR, et  al. Infections in the neutropenic patient – new views of an old problem. Hematology Am Soc Hematol Educ Program. 2001;113–39. 27. Lautenbach E et al. Changes in the prevalence of vancomycin-resistant enterococci in response to antimicrobial formulary interventions: impact of progressive restrictions on use of vancomycin and thirdgeneration cephalosporins. Clin Infect Dis. 2003;36(4):440–6. 28. Safdar N, Maki DG. The commonality of risk factors for nosocomial colonization and infection with antimicrobial-resistant Staphylococcus aureus, enterococcus, gram-negative bacilli, Clostridium difficile, and Candida. Ann Intern Med. 2002;136(11):834–44. 29. Gonzalez-Barca E et al. Prognostic factors influencing mortality in cancer patients with neutropenia and bacteremia. Eur J Clin Microbiol Infect Dis. 1999;18(8):539–44. 30. Pagano L et al. Bacteremia in patients with hematological malignancies. Analysis of risk factors, etiological agents and prognostic indicators. Haematologica. 1997;82(4):415–9. 31. Norgaard M et al. Risk of bacteraemia and mortality in patients with haematological malignancies. Clin Microbiol Infect. 2006;12(3): 217–23. 32. Bochud PY et al. Bacteremia due to viridans streptococcus in neutropenic patients with cancer: clinical spectrum and risk factors. Clin Infect Dis. 1994;18(1):25–31. 33. Elting LS, Bodey GP, Keefe BH. Septicemia and shock syndrome due to viridans streptococci: a case-control study of predisposing factors. Clin Infect Dis. 1992;14(6):1201–17. 34. Tunkel AR, Sepkowitz KA. Infections caused by viridans streptococci in patients with neutropenia. Clin Infect Dis. 2002;34(11):1524–9. 35. Pizzo PA et al. Empiric antibiotic and antifungal therapy for cancer patients with prolonged fever and granulocytopenia. Am J Med. 1982;72(1):101–11. 36. Hughes WT et  al. 1997 Guidelines for the use of antimicrobial agents in neutropenic patients with unexplained fever. Infectious Diseases Society of America. Clin Infect Dis. 1997;25(3):551–73. 37. Edmond MB et al. Nosocomial bloodstream infections in United States hospitals: a three-year analysis. Clin Infect Dis. 1999;29(2):239–44. 38. Pfaller MA et  al. International surveillance of bloodstream infections due to Candida species: frequency of occurrence and in vitro susceptibilities to fluconazole, ravuconazole, and voriconazole of isolates collected from 1997 through 1999 in the SENTRY antimicrobial surveillance program. J Clin Microbiol. 2001;39(9):3254–9. 39. Anttila VJ et  al. Hepatosplenic candidiasis in patients with acute leukemia: incidence and prognostic implications. Clin Infect Dis. 1997;24(3):375–80. 40. Kontoyiannis DP, Bodey GP. Invasive aspergillosis in 2002: an update. Eur J Clin Microbiol Infect Dis. 2002;21(3):161–72.

37 41. Pagano L et al. The epidemiology of fungal infections in patients with hematologic malignancies: the SEIFEM-2004 study. Haematologica. 2006;91(8):1068–75. 42. Walsh TJ, Hiemenz JW, Anaissie E. Recent progress and current problems in treatment of invasive fungal infections in neutropenic patients. Infect Dis Clin North Am. 1996;10(2):365–400. 43. Roden MM et  al. Epidemiology and outcome of zygomycosis: a review of 929 reported cases. Clin Infect Dis. 2005;41(5):634–53. 44. Kontoyiannis DP et al. Zygomycosis in a tertiary-care cancer center in the era of Aspergillus-active antifungal therapy: a case-control observational study of 27 recent cases. J Infect Dis. 2005;191(8): 1350–60. 45. Chandrasekar PH. Fungi other than Candida and Aspergillus. In: Bowden RA, editor. Infections in oncology patients. Philadelphia, PA: Martin Dunitz; 2003. 46. Bogomolski-Yahalom V, Matzner Y. Disorders of neutrophil function. Blood Rev. 1995;9(3):183–90. 47. Serbina NV et  al. Monocyte-mediated defense against microbial pathogens. Annu Rev Immunol. 2008;26:421–52. 48. Wade JC. Viral infections in patients with hematological malignancies. Hematology Am Soc Hematol Educ Program. 2006;368–74. 49. Huang H et al. Lamivudine for the prevention of hepatitis B virus reactivation after high-dose chemotherapy and autologous hematopoietic stem cell transplantation for patients with advanced or relapsed non-Hodgkin’s lymphoma single institution experience. Expert Opin Pharmacother. 2009;10(15):2399–406. 50. Uchiyama M, Tamai Y, Ikeda T. Low-dose acyclovir against reactivation of varicella zoster virus after unrelated cord blood transplantation. Int J Infect Dis. 2009;14(5):e451–2. 51. Waecker Jr NJ et al. Nosocomial transmission of Mycobacterium bovis bacille Calmette-Guerin to children receiving cancer therapy and to their health care providers. Clin Infect Dis. 2000;30(2): 356–62. 52. Pei SN et al. Reactivation of hepatitis B virus following rituximabbased regimens: a serious complication in both HBsAg-positive and HBsAg-negative patients. Ann Hematol. 2009;89(3):255–62. 53. Gabriel DA et  al. The effect of oral mucositis on morbidity and mortality in bone marrow transplant. Semin Oncol. 2003;30(6 Suppl 18):76–83. 54. Sonis ST. The biologic role for nuclear factor-kappaB in disease and its potential involvement in mucosal injury associated with antineoplastic therapy. Crit Rev Oral Biol Med. 2002;13(5):380–9. 55. Sonis ST et  al. Perspectives on cancer therapy-induced mucosal injury: pathogenesis, measurement, epidemiology, and consequences for patients. Cancer. 2004;100(9 Suppl):1995–2025. 56. Schimpff SC et al. Origin of infection in acute nonlymphocytic leukemia. Significance of hospital acquisition of potential pathogens. Ann Intern Med. 1972;77(5):707–14. 57. Weinstock DM et al. Colonization, bloodstream infection, and mortality caused by vancomycin-resistant enterococcus early after allogeneic hematopoietic stem cell transplant. Biol Blood Marrow Transplant. 2007;13(5):615–21. 58. David DS et al. Visceral varicella-zoster after bone marrow transplantation: report of a case series and review of the literature. Am J Gastroenterol. 1998;93(5):810–3. 59. Ravandi F, Anaissie E, O’Brien S. Infections in chronic leukemias and other hematological malignancies. In: Wingard JR, Bowden RA, editors. Infections in oncology patients. Philadelphia, PA: Martin Dunitz; 2003. 60. Molica S, Levato D, Levato L. Infections in chronic lymphocytic leukemia. Analysis of incidence as a function of length of followup. Haematologica. 1993;78(6):374–7. 61. Tam CS et al. A new model for predicting infectious complications during fludarabine-based combination chemotherapy among patients with indolent lymphoid malignancies. Cancer. 2004; 101(9):2042–9.

38 62. Anaissie EJ et al. Infection in patients with chronic lymphocytic leukemia treated with fludarabine. Ann Intern Med. 1998;129(7):559–66. 63. Lungman P. Viral infections: current diagnosis and treatment. Hematol J. 2004;5:S63–8. 64. Sandherr M et al. Antiviral prophylaxis in patients with haematological malignancies and solid tumours: Guidelines of the Infectious Diseases Working Party (AGIHO) of the German Society for Hematology and Oncology (DGHO). Ann Oncol. 2006;17(7):1051–9. 65. O’Brien SM et al. Results of the fludarabine and cyclophosphamide combination regimen in chronic lymphocytic leukemia. J Clin Oncol. 2001;19(5):1414–20. 66. Cavalli-Bjorkman N et al. Fatal adenovirus infection during alemtuzumab (anti-CD52 monoclonal antibody) treatment of a patient with fludarabine-refractory B-cell chronic lymphocytic leukemia. Med Oncol. 2002;19(4):277–80. 67. Kennedy B, Hillmen P. Immunological effects and safe administration of alemtuzumab (MabCampath) in advanced B-cLL. Med Oncol. 2002;19(Suppl):S49–55. 68. Rai KR et al. Alemtuzumab in previously treated chronic lymphocytic leukemia patients who also had received fludarabine. J Clin Oncol. 2002;20(18):3891–7. 69. Laurenti L et al. Cytomegalovirus reactivation during alemtuzumab therapy for chronic lymphocytic leukemia: incidence and treatment with oral ganciclovir. Haematologica. 2004;89(10):1248–52. 70. Rawstron AC et  al. Early prediction of outcome and response to alemtuzumab therapy in chronic lymphocytic leukemia. Blood. 2004;103(6):2027–31. 71. Rieger K et  al. Efficacy and tolerability of alemtuzumab (CAMPATH-1H) in the salvage treatment of B-cell chronic ­lymphocytic leukemia – change of regimen needed? Leuk Lymphoma. 2004;45(2):345–9. 72. Wendtner CM et  al. Consolidation with alemtuzumab in patients with chronic lymphocytic leukemia (CLL) in first remission – ­experience on safety and efficacy within a randomized multicenter phase III trial of the German CLL Study Group (GCLLSG). Leukemia. 2004;18(6):1093–101. 73. Lin TS et al. Filgrastim and alemtuzumab (Campath-1H) for refractory chronic lymphocytic leukemia. Leukemia. 2005;19(7):1207–10. 74. Lundin J et al. Phase II trial of subcutaneous anti-CD52 monoclonal antibody alemtuzumab (Campath-1H) as first-line treatment for patients with B-cell chronic lymphocytic leukemia (B-CLL). Blood. 2002;100(3):768–73. 75. Keating MJ et al. Therapeutic role of alemtuzumab (Campath-1H) in patients who have failed fludarabine: results of a large international study. Blood. 2002;99(10):3554–61.

G. Papanicolaou and J. Mehta 76. Keating MJ et  al. Long-term follow-up of patients with chronic lymphocytic leukemia (CLL) receiving fludarabine regimens as ­initial therapy. Blood. 1998;92(4):1165–71. 77. Keating MJ et  al. Early results of a chemoimmunotherapy regimen of fludarabine, cyclophosphamide, and rituximab as initial therapy for chronic lymphocytic leukemia. J Clin Oncol. 2005;23(18):4079–88. 78. Tam C et al. Early and late infectious consequences of adding rituximab to fludarabine and cyclophosphamide in patients with indolent lymphoid malignancies. Haematologica. 2005;90(5):700–2. 79. Blade, J, Rosinol L. Complications of multiple myeloma. Hematol Oncol Clin North Am. 2007;21(6):1231–46, xi. 80. Hargreaves RM et al. Immunological factors and risk of infection in plateau phase myeloma. J Clin Pathol. 1995;48(3):260–6. 81. Savage DG, Lindenbaum J, Garrett TJ. Biphasic pattern of bacterial infection in multiple myeloma. Ann Intern Med. 1982;96(1): 47–50. 82. San Miguel JF et al. Bortezomib plus melphalan and prednisone for initial treatment of multiple myeloma. N Engl J Med. 2008;359(9): 906–17. 83. Lortholary O et al. Invasive aspergillosis as an opportunistic infection in nonallografted patients with multiple myeloma: a European Organization for Research and Treatment of Cancer/Invasive Fungal Infections Cooperative Group and the Intergroupe Francais du Myelome. Clin Infect Dis. 2000;30(1):41–6. 84. Fisher RI et al. Persistent immunologic abnormalities in long-term survivors of advanced Hodgkin’s disease. Ann Intern Med. 1980;92(5):595–9. 85. Dalton JA et  al. Cutaneous T-cell lymphoma. Int J Dermatol. 1997;36(11):801–9. 86. Posner LE et al. Septicemic complications of the cutaneous T-cell lymphomas. Am J Med. 1981;71(2):210–6. 87. Axelrod PI, Lorber B, Vonderheid EC. Infections complicating mycosis fungoides and Sezary syndrome. JAMA. 1992;267(10): 1354–8. 88. Thursky KA et al. Spectrum of infection, risk and recommendations for prophylaxis and screening among patients with lymphoproliferative disorders treated with alemtuzumab. Br J Haematol. 2006;132(1):3–12. 89. National Comprehensive Cancer Network. Clinical practice ­guidelines in oncology: prevention and treatment of cancer related infections (v.2.2009). Jenkintown, PA: NCCN; 2009. 90. Marshall BG et al. Increased inflammatory cytokines and new collagen formation in cutaneous tuberculous and sarcoidosis. Thorax. 1996;51(12):1253–61.

Chapter 4

Infections in Solid Tumor Patients Alison G. Freifeld

Abstract  Over 90% of the 1.4 million new cases of cancer diagnosed in the United States in 2008 were due to solid tumors, with predominant sites being lung, breast, prostate, colorectal, bladder, and uterine cancers. While it is clear to practicing oncologists that solid tumor patients are generally at lower risk for infection-related complications overall, infections are certainly not rare in this population. Common foci include intravascular catheter-related bacteremia, pneumonias, wound and skin/soft tissue infections, and fever associated with chemotherapy-induced neutropenia. Nonetheless, there is little published data examining the incidence or characteristics of infections in solid tumor patients. This is not only because infection is relatively uncommon in solid tumor patients but also because sites, pathogens, and severity will vary, to a large extent, with tumor location, natural history, and the type and intensity of anticancer therapy. This variability precludes a neat summary of all the bacterial, viral, and fungal infections that occur in the solid tumor group as a whole. Instead, observational series and anecdotal reports have lead to the recognition of patterns of infection that may be considered “typical” for specific solid tumor types, or that are associated with certain antitumor treatment regimens. The goal of this chapter is to familiarize the physician with these infection profiles, so they may identify and manage them promptly and effectively. Keywords  Infection • Neutropenia • Catheter-related infections • Postsurgical wound infections • Bacteremia • Colon cancer • Breast cancer • Lung cancer

Introduction Over 90% of the 1.4 million new cases of cancer diagnosed in the United States in 2008 were due to solid tumors, with predominant sites being lung, breast, prostate, colorectal, bladder,

A.G. Freifeld (*) Department of Medicine, University of Nebraska Medical Center, Omaha, NE 68198-5400, USA e-mail: [email protected]

and uterine cancers [1]. Hematologic malignancies accounted for less than 10% of new cancers in the same year (approximately 5% lymphomas, 3% leukemias, and 1.5% multiple myelomas), yet the levels of morbidity, mortality, and overall healthcare resource utilization among patients with hematologic cancers far exceed those for solid tumor patients [2, 3]. Duration of hospitalization and inpatient mortality tends to be significantly greater in leukemic patients with fever and neutropenia than for those with solid tumors [3]. In a recent multicenter European study, bloodstream infections were found to be nearly 3 times more common in lymphoma and leukemia patients with fever and neutropenia than in patients with solid tumors [4]. While it is clear to practicing oncologists that solid tumor patients are generally at lower risk for infection-related complications overall, infections are certainly not rare in this population. Common foci include intravascular catheter-related bacteremia, pneumonias, wound and skin/soft tissue infections, and fever associated with chemotherapy-induced neutropenia. Nonetheless, there is little published data examining the incidence or characteristics of infections in solid tumor patients. This is not only because infection is relatively uncommon in solid tumor patients but also because sites, pathogens, and severity will vary, to a large extent, with tumor location, natural history, and the type and intensity of anticancer therapy. This variability precludes a neat summary of all the bacterial, viral, and fungal infections that occur in the solid tumor group as a whole. Instead, observational series and anecdotal reports have led to the recognition of patterns of infection that may be considered “typical” for specific solid tumor types, or that are associated with certain antitumor treatment regimens. The goal of this chapter is to familiarize the physician with these infection profiles, so they may identify and manage them promptly and effectively.

Infection Risks and Pathogens In the patient with hematologic malignancy, normal immune mediator cells are replaced by malignant clones that fail to perform protective immunologic tasks. Serial cycles of

A. Safdar (ed.), Principles and Practice of Cancer Infectious Diseases, Current Clinical Oncology, DOI 10.1007/978-1-60761-644-3_4, © Springer Science+Business Media, LLC 2011

39

40

i­ntensive chemotherapy with corresponding prolonged ­periods of neutropenia further contribute to profound immunologic compromise that allow for opportunistic infections to advance. By contrast, defects in immune responses are far less frequent among solid tumor patients whose immune function is unaffected by the underlying disease, and less intensive cytoreductive therapies are more common. Breeches in physical defense barriers are a common ­predisposing factor leading to infection in the solid tumor patient. Tumor infiltration across tissue planes with obstruction of a normally patent conduits of body secretions, such as colon, biliary tract, or bronchus, can lead to postobstructive infections. Tumor debulking or diagnostic surgeries with attendant anatomic disruptions and poor surgical wound healing will also contribute risks. Radiation therapy can also lead to tissue fragility and damage and impaired wound healing. Concurrent use of chemotherapy that enhances the radiosensitivity of tumors increases the chance of mucosal injury and neutropenia [5]. Disruptions of skin and mucous membrane integrity allow for skin and gastrointestinal commensals such as staphylococci, streptococci, enteric Gram-negative bacilli, and Candida ­species to gain access to surrounding tissue or to the bloodstream. These components of colonizing flora are common ­etiologies of infections in the solid tumor patient (Table 4.1). Cytotoxic chemotherapy for solid tumors will often occur in repeated cycles, as with hematologic cancer treatments, but the attendant periods of chemotherapy-induced ­neutropenia are comparatively very mild (rarely yielding an ­absolute neutrophil count 100 CFU/mL from CVC tip

Labor intensive and expensive

Cultures drawn from catheters may be falsely negative if the antibiotics are given intraluminally and also does not evaluate patients with positive CVC cultures and negative peripheral blood cultures

Cultures only the organisms on the external surface and does not culture organisms embedded in the biofilm May over release the biofilm microorganisms that might not be clinically relevant; whereas, relevant planktonic organisms might be killed

116

I. Al Wohoush et al.

Quantitative Catheter Segment Culture

Maximal Sterile Barrier

To overcome the roll-plate limitation of missing the organisms colonizing the catheters’ lumen, several methods such as centrifugation, vortexing, and sonication have been used [36–38]. The catheter segments are immersed in broth and flushed, followed by serial dilutions and surface plating on blood agar. A count of greater than or equal 100 CFU is considered to be associated with infection. The diagnosis of CRBSI is established if a peripheral blood culture yielded the same organism grown from the catheter tip culture [39]. Brun-Buisson et  al. suggested a modified version of this method where the segments are vortexed rather than flushed. He reported a sensitivity of 97.5% and specificity of 88% [40]. Raad et  al. compared the roll-plate culture with the catheter sonication method, and yielded sensitivities of 78 and 93% respectively and specificities of 88 and 94% respectively [34]. Widmer and Frei compared the sonication with the roll-plate method in short-term catheters and found similar sensitivities and specificities [41]. However, for long-term catheters, the sonication method was found to have higher sensitivity than the roll-plate method [6]. The pooled sensitivity and specificity of quantitative catheter segment culture for short-term catheters were 82 and 89% respectively, and 83 and 97% for long-term catheters [23]. The disadvantage of this method is that it releases the biofilm microorganisms that might not be clinically relevant; whereas, relevant planktonic organisms might be killed.

The following five evidence-based procedures are recommended by the CDC and identified as having the greatest effect on the rate of CRBSI: hand washing, using full-barrier precautions during the insertion of CVC, cleaning the skin with chlorhexidine, avoiding the femoral site if possible, and removing unnecessary catheters. These five elements are particularly important in nontunneled catheters and PICCs, which are usually inserted out of the operating room; and hence, their insertion may not be subject to the strict sterile atmosphere of an operating room. Pronovost et  al. [42] reported a decrease of median rate of catheter-related infections from 2.7/1,000 catheter-days at baseline to 0 within the first 3 months of applying the mentioned five elements, and a reduction in the rate of CRBSI of 66% at 16–18 months after implementation. Other studies reported a decrease in the rate of CRBSI from 0.5/1,000 to 0.02/1,000 catheter-days after applying the maximal sterile barrier precautions consisting of wearing sterile gown, gloves and cap, and using a large drape during the insertion of catheters.

Prevention of Catheter-Related Infections An ounce of prevention is worth a pound of cure, and this is completely true in medical practice. Not only CRBSIs may require the removal of the catheter consequently interfering with the treatment plan but also they are associated with high morbidity and mortality rates, as well increase cost of care. Therefore, the prevention of CRBSI is of paramount importance (Table  10.2). Successful preventive strategies should focus on controlling all factors that could lead to the colonization of CVC by microorganisms. Traditional measures for the prevention of catheter-related infections, recommended by the healthcare infection control practices advisory committee (HICPAC) guidelines, include education of health care workers on proper catheter insertion and maintenance, routine monitoring of institutional rates of CRBSI, hand hygiene, use of a dedicated infusion therapy team, use of sterile dressings, avoidance of femoral insertion, and removal of the vascular catheter as soon as possible [2]. In the next section, we will review major strategies for the prevention of catheter-related infections.

Tunneling Tunneling the catheters creates a fibrous tissue around the dacron cuff (which is used to anchor the catheter in place), and this tissue will act as a barrier against the migration of microorganisms. A recent study comparing the tunneled and nontunneled catheters showed that the infection rate was 1.9 per catheter-days in the nontunneled group vs. 0.7 per catheter-days in the tunneled catheter group. Another study comparing these two groups failed to demonstrate a difference between them, and showed a rate of 0.22/1,000 ­catheter-days was reported in the nontunneled catheter group vs. 0.20/1,000 catheter-days in the tunneled group. More studies are needed to prove the efficacy of tunneled catheters in preventing catheter-related infections; especially since tunneling a catheter is a surgical procedure that may cost an additional $2,500.

Antimicrobial Coating of Catheters Coating the catheters with antibiotics leads to a slow release of the antibiotics that prevent the adherence of the microorganisms to the catheter surfaces and preclude the initial formation of the biofilm [43]. Many generations and types of antibiotic-coated catheters were studied with different rates of success in preventing catheter-related infections.

10  Catheter-Related Infections in Cancer Patients

117

Table 10.2  Prevention of catheter related blood stream infection Method Advantages Maximal sterile barrier

Catheter tunneling

Antiseptic catheters. First and second generation Antibioticsimpregnated catheters

Antimicrobial lock solution

Hand washing, using full-barrier precautions during the insertion of central venous catheter, cleaning the skin with chlorhexidine, avoiding the femoral site if possible, and removing unnecessary catheters It creates a fibrous tissue around the dacron cuff, which acts as a barrier against the migration of microorganisms They are coated only on the external surface of the catheter using CHXSSD in first generation External and luminal surfaces are impregnated in the second generation It is a polyurethane and silicone catheter impregnated with minocycline and rifampin on both the external and luminal surfaces of the catheter

Disadvantages

It lowers the rates of CRBSI

It requires continuous staff education and reinforcement Role of all components have not been determined

The tunneled catheters are long-term ones

Costly, requires surgical procedure or interventional radiology for insertion and efficacy still not proven completely

Can lower the incidence of CRBSI in short-term catheters

Failed to show a decrease in CRBSI in long-term catheters Inferior efficacy to CVC impregnated with minocycline-rifampin It has no effect on catheter-related candidemia

It decreases the incidence of CRBSI significantly It is not associated with increased resistance for minocycline or rifampin The catheter lumen is filled with 2–3 mL Using EDTA with minocycline Use of vancomycin is associated with increased risk for resistance may have a synergistic of a combination of anticoagulant and activity against methicillin Vancomycin has no coverage against gram an antimicrobial agent resistant staphylococci, negative bacteria gram negative bacilli, and And limited activity against organisms Candida albicans embedded in the biofilm

Antiseptic Catheters These catheters are impregnated with chlorhexidine and silver sulfadiazine. Two generations were developed in order to lower the rates of CRBSIs. The first generation of the chlorhexidine-silver sulfadiazine was coated only on the external surface of the catheter. Different prospective randomized clinical trials [2, 6, 27–38, 44–48] have evaluated this generation of chlorhexidine-sulfadiazine catheters, and most of them showed a reduction in the CRBSI but only two trials reported a significant reduction in CRBSI [49, 50]. It is estimated that the use of these catheters in patients at high risk for catheter-related infection can save $68–391 per insertion [51]. Several studies failed to show a decrease in catheterrelated infections in long-term catheters. This lack of longterm efficacy is based on the limited antimicrobial durability of these catheters (around 7 days in serum) and the fact that only the outer surface of the catheter was impregnated, consequently providing no protection against luminal colonization [44]. As a conclusion, the first generation of the chlorhexidine-sulfadiazine impregnated catheters can reduce the risk of catheter-related infection in short-term catheters, but cannot reduce the risk of CRBSI in long-term catheters. The second generation of these catheters was impregnated on the external and the luminal surfaces of the catheter. In one study, the use of these catheters decreased the catheter colonization from 11/1,000 to 3.6/1,000 catheter-days; but

failed to decrease the rate of CRBSI’s [52]. Three subsequent studies also failed to prove a decrease in the rate of CRBSIs [53–55]. The use of these catheters might be cost effective in high-risk patients such as ICU patients, burn patients, and other patient populations in which the rate of infection exceeds 3.3/1,000 catheter-days [4].

Antibiotic-Coated Catheter The only FDA approved antibiotic-coated catheter is a ­polyurethane catheter impregnated with minocycline and rifampin on both the external and luminal surfaces of the catheter. Two trials demonstrated that the use of minocyclinerifampin coated catheters is associated with lower rates of CRBSIs compared to the use of uncoated catheters [56, 57]. A prospective, randomized, double blinded study comparing the first generation of chlorhexidine-sulfadiazine coated catheters and minocycline-rifampin coated catheters showed that Minocycline-rifampin coated catheters were 12-fold less likely to be associated with CRBSI and threefold less likely to be colonized [56, 58]. In a recent study, Wright et al. showed a reduction in ICU stay and ICU mortality after the introduction of antibiotic-coated catheters, but reported an increase in rifampin resistance among Staphylococcus epidermis isolates [59]. However, data from MD Anderson cancer center concluded that after 4 years, and more than 24,000 catheter-days,

118

I. Al Wohoush et al.

of using antibiotic-coated catheters in stem cell transplant patients, staphylococcus isolates remained highly susceptible to minocycline and rifampin [60]. Raad et  al. reported in a 7-year study that the resistance to tetracycline and rifampin decreased 44 and 56% respectively among coagulase negative staphylococci; similarly, the resistance patterns to tetracycline and rifampin among MRSA clinical isolates had a significant decrease of 42 and 67% respectively. Several other studies have shown that the risk of minocycline and rifampin is very low [61, 62]. The risk to develop minocycline and rifampin resistance is low because both require different mutation mechanisms at a cumulative frequency of approximately 1:1012 bacteria. Such bacterial concentrations are only found in the gastrointestinal tract and are unlikely to be observed in the surrounding subcutaneous environment of the catheters. Moreover, antibiotics delivered by antibiotic-coated catheters are not detectable in the blood [63]. The authors recently suggested that it is mandatory to combine the maximal sterile barrier precautions and antimicrobial-impregnated catheters to achieve the desired goal of “zero tolerance” [64]. The use of the aseptic techniques bundle, including maximal sterile barrier precautions, prevents contamination of the CVC. However, the use of antimicrobial-coated CVC will prevent biofilm colonization of the external and the internal surfaces of the CVCs during the insertion and subsequently during the time it remains in place.

Vancomycin prophylactically should be avoided to minimize the risk of emergence of vancomycin-resistant organisms, besides it does not cover for gram negative bacteria and Candida species. Chelators as EDTA have an anticoagulant activity similar to heparin and have been found to enhance the activity of antimicrobial drugs against organisms in the biofilm [71–74]. Raad et al. used EDTA with minocycline as prophylaxis in three patients [75], and showed a synergistic activity against methicillin-resistant staphylococci, gram negative bacilli, and Candida albicans and a cidal effect against bacteria in the biofilm.

Management of Catheter-Related Blood Stream Infections Antibiotic therapy for CRBSIs should be initiated empirically. The decision to remove the catheter has to be made cautiously since it is often assumed to be the source of infection, and there is tendency to remove the catheter even before determining whether it is the source of infection or not. The above decisions depend mainly on the type of the organism causing the CRBSI (Table 10.3). Usually vancomycin is the recommended drug for the empirical treatment for CRBSI, with the exceptions of hospital with predominance of MRSA, or when vancomycin MIC >2, in which case other agents such as Daptomycin should be used [5, 6].

Antimicrobial Lock Solutions Heparin has been used as an antithrombotic agent in catheters after several studies showed that heparin can reduce the catheter-related infections [65]. However, subsequent studies showed that heparin is as effective as saline in preventing phlebitis and enhances the staphylococcal biofilm formation [66]. Therefore, a novel technology was developed, in which the catheter lumen is flushed and filled with 2–3  mL of a solution that is usually a combination of an anticoagulant and an antimicrobial agent such as vancomycin. Few studies showed a decrease in the rate of CRBSI after using heparinvancomycin as a lock solution [67, 68], other studies failed to show a significant benefit [69, 70]. However, using

Coagulative Negative Staphylococci Coagulative negative Staphylococci (CoNS) are the most common cause of CRBSI, but at the same time they are a common colonizer of the human skin. Most patients have a benign clinical course; however occasionally, patients may develop frank sepsis with poor outcome [76–78]. A definite diagnosis of CoNS bacteremia requires at least two positive blood cultures, one of them obtained from a peripheral vein. CoNS bacteremia is treated with antibiotics for 5–7 days if the catheter is removed, and for 10–14 days in combination with antibiotic lock therapy if the catheter is still in place.

Table 10.3  Management of catheter related blood stream infection according to the causative agent CoNS S. aureus Enterococci Catheter removal Alternative for catheter removal

Duration of treatment

Occasionally Antibacterial lock solution Exchange over a guide wire for a new antimicrobial-impregnated catheter 5–7 days if catheter is removed 10–14 days + antimicrobial lock if catheter is retained

Gram negative

Candida Spp.

Yes

Yes

Yes

Yes ETOH lock solution

14 days

7–14 days

7–14 days

14 days

10  Catheter-Related Infections in Cancer Patients

Staphylococcus aureus

119

S. aureus is associated with a high rate of complications [79], most commonly septic thrombosis of large veins [80] which mainly occurs among patients with solid tumors [81]. The most serious complication associated with S. aureus CRBSI is endocarditis, thus it is always necessary for every patient with S. aureus bacteremia and a persistent fever or bacteremia to undergo a transesophageal echocardiography to exclude endocarditis [11, 82]. Many prospective studies have shown that removal of the CVC in patients with S. aureus CRBSI is associated with a more rapid response to therapy and a lower relapse rate [79, 83, 84]. Therefore, it is essential to remove the catheter in every patient with S. aureus CRBSI unless there is a major contraindication (i.e., no another venous access) [85, 86]. The type of antibiotics used should be based on the susceptibility of S. aureus. Semisynthetic antistaphylococcal penicillin or first generation cephalosporins are the first choice for patients with methicillin sensitive S. aureus, while vancomycin and daptomycin are the drugs of choice in patients with methicillin resistant S. aureus CRBSI [83, 84]. The usual duration of treatment of S. aureus CRBSI is 4–6 weeks, but it can be shortened (>14 days) if the patient is not diabetic, not immunocompromised, has no prosthetic intravascular device, has no complications associated with S. aureus CRBSI, and the catheter is removed [85].

[92, 93]; therefore, rapid diagnosis and treatment are essential in the management of catheter-related candidemia. Candida empiric coverage should be used in septic patients with any of the following risk factors: total parenteral nutrition, prolonged broad spectrum antibiotics, hematological malignancy, bone marrow transplant, femoral catheterization, and Candida colonization at multiple sites. Several studies evaluated the impact of catheter removal on the outcome of the candidemia, and showed that catheter removal is associated with a better outcome [94–97]. Another study showed that catheter retention was found to be an independent variable risk of death in multivariate analysis independent of persistent neutropenia [95]. Raad et  al. showed that CVC retention more than 72  h after the onset of candidemia is associated with poor outcome in patients with catheter-related candidemia [98]. Therefore, the catheter should be removed within the first 72 h in case of CRBSI due to Candida, and antifungal agents should be administered for at least 14 days according to the IDSA guidelines [91]. A recent study showed that fluconazole was shown to be equal in efficacy to amphotericin B in the treatment of candidemia with a better safety profile [99]. More recent studies showed that Echinocandin such as caspofungin and anidulafungin are equivalent or superior to fluconazole for the treatment of CRBSI due to Candida [99]. Fluconazole or any Echinocandins are considered as a first line in the treatment of CRBSI due to Candida.

Gram Negative Bacilli

Micrococcus

Gram negative bacilli are not the usual suspects in CRBSI. However, gram negative bacillary CRBSI caused by organisms such as Klebsiella pneumoniae, Enterobacter spp., Pseudomonas spp., Acinetobacter spp., and Stenotro­ phomonas species have been reported [87, 88]. The empiric gram negative coverage should only be considered in specific groups of patients such as, neutropenic patients, severely ill patients with sepsis, or patients known to be colonized with these pathogens [81, 89, 90]. Hanna et  al. showed that CRBSI caused by gram negative bacilli was associated with high rate of relapse if the catheter was not removed, whereas CVC removal was associated with only 1% risk of relapse [88]. Management of gram negative CRBSI consists of removing the CVC and treating with active antibiotics against gram negative bacilli such as gentamicin, amikacin, or ceftazidime [89, 91].

Micrococcus species have the ability to adhere to medical devices and cause associated infections, particularly CRBSIS [100]. These infections are more likely to persist in patients with prior hemodialysis, the absence of prior GCSF therapy, longer catheter retention intervals, and longer catheter dwell time [101]. A recent study showed that 100% of Micrococcus isolates were susceptible to vancomycin, 95% to ­trimethoprim-sulfamethoxazole, 84% to rifampin, and 41% to oxacillin [102].

Candida Species Catheter-related candidemia may be associated with serious complications such as septic thrombosis and endocarditis

Exchange over a Guide Wire Catheter removal is required in almost all cases of CRBSI. However, in some instances (e.g., no another vascular access) removing the catheter may jeopardize the patient safety. Thus exchanging the infected catheter over a guide wire was suggested as an alternative method in treatment. A recent study showed that exchanging the infected catheter with an uncoated one may result in a cross infection in the new catheter. Hence, exchanging the infected catheter with a minocycline-rifampin (M/R) impregnated catheter seemed to

120

prevent the “cross infection.” Authors have showed that exchanging the infected catheters with those M/R impregnated was associated with lower morbidity and mortality rates when compared to those of uncoated catheters. An improved overall response rate, risk of mechanical failure and infection recurrence were also noted [103].

References 1. Maki DG, Mermel LA. Infections due to infusion therapy. In: Bennet JV, Brachaman PS, editors. Hospital infections. Philadelphia: Lippincott-Raven; 1998. p. 689–724. 2. O’Grady NP, Alexander M, Dellinger EP, et al. Guidelines for the prevention of intravascular catheter related infections. MMWR Recomm Rep. 2002;51:1–29. 3. National Nosocomial Infections Surveillance System. National nosocomial infections (NNIS) system report, data summary from January 1992 through June 2004, issued October 2004. Am J Infect Control. 2004;32:470–85. 4. Maki DG, Stolz SM, Wheeler S, Mermel LA. Prevention of central venous catheter-related bloodstream infection by use of an antiseptic impregnated catheter: a randomized controlled trial. Ann Intern Med. 1997;127:257–66. 5. Mermel LA, McCormick RD, Springman SR, Maki DG. The pathogenesis and epidemiology of catheter-related infection with pulmonary artery Swan-Ganz catheters: a prospective study utilizing molecular subtyping. Am J Med. 1991;91(Suppl 3B):197S–205. 6. Raad I, Costerton W, Sabharwal U, Sacilowski M, Anaissie E, Bodey GP. Ultrastructural analysis of indwelling vascular catheters: a quantitative relationship between luminal colonization and duration of placement. J Infect Dis. 1993;168:400–7. 7. Stiges-Serra A, Puig P, Linares J, et  al. Hub colonization as the initial step in an outbreak of catheter-related sepsis due to coagulase negative staphylococci during parenteral nutrition. J Parenter Enteral Nutr. 1984;8:668–72. 8. Salzman MB, Isenberg HD, Shapiro JF, et al. A prospective study of the catheter hub as the portal of entry for microorganisms causing catheter-related sepsis in neonates. J Infect Dis. 1993;167:487–90. 9. Centers for Disease Control. Nosocomial bacteremia associated with intravenous fluid therapy. MMWR. 1971;20 (Suppl 9):S1–2. 10. Maki DG, Rhame FS, Mackel DC, et al. Nation-wide epidemic of septicemia caused by contaminated intravenous products. Am J Med. 1976;60:471–85. 11. Mermel LA, Farr BM, Sherertz RJ, et al. Guidelines for the management of intravascular cathéter related infections. Clin Infect Dis. 2001;32:1249–72. 12. Safdar N, Maki DG. Inflammation at the insertion site is not predictive of catheter-related bloodstream infection with short-term, noncuffed central venous catheters. Crit Care Med. 2002;30:2632–5. 13. Chatzinikolau I, Hanna H, Hachem R, Alakech B, Tarrabd J, Raad I. Differential quantitative blood culture for the diagnosis of catheter related blood stream infections associated with short and long term catheters: a prospective study. Diagn Microbial Infect Dis. 2004;50:167–72. 14. Douard MC, Clementi E, Arlet G, et al. Negative catheter-tip culture and diagnosis of catheter-related bacteraemia. Nutrition. 1994;10:397–404. 15. Capdevila JA, Planes AM, Palomar M, et al. Value of differential quantitative blood cultures in the diagnosis of catheter-related sepsis. Eur J Clin Microbiol Infect Dis. 1992;11:403–7. 16. Douard MC, Arlet G, Longuet P, et al. Diagnosis of venous access port-related infections. Clin Infect Dis. 1999;29:1197–202.

I. Al Wohoush et al. 17. Flynn PM, Shenep JL, Barrett FF. Differential quantitation with a commercial blood culture tube for diagnosis of catheter-related infection. J Clin Microbiol. 1988;26:1045–6. 18. Blot F, Schmidt E, Nitenberg G, et al. Earlier positivity of central venous versus peripheral-blood cultures is highly predictive of catheter-related sepsis. J Clin Microbiol. 1998;36:105–9. 19. Blot F, Nitenberg G, Chachaty E, et  al. Diagnosis of catheter related bacteraemia: a prospective comparison of the time to positivity of hub-blood versus peripheral-blood cultures. Lancet. 1999;354:1071–7. 20. Raad I, Hanna HA, Alakech B, Chatzinikolaou I, Johnson MM, Tarrand J. Differential time to positivity: a useful method for diagnosing catheter-related bloodstream infections. Ann Intern Med. 2004;140:18–25. 21. Raad I, Hanna HA, Alakech B, et al. Differential time to positivity: a useful method for diagnosing catheter-related bloodstream infections. Ann Intern Med. 2004;140:18–25. 22. Acuna M, O’Ryan M, Cofre J, Alvarez I, Benadof D, Rodriguez P, et  al. Differential time to positivity and quantitative cultures for noninvasive diagnosis of catheter related blood stream infection in children. Pediatr Infect Dis J. 2008;27:681–5. 23. Safdar N, Fine JP, Maki DG. Meta-analysis: methods for diagnosing intravascular device-related bloodstream infection. Ann Intern Med. 2005;142:451–66. 24. Hanna R, Raad II. Diagnosis of catheter-related bloodstream infection. Curr Infect Dis Rep. 2005;7:413–9. 25. Maki DG, Weise CE, Sarafin HW. A semiquantitative culture method for identifying intravenous-catheter-related infection. N Engl J Med. 1977;296:1305–9. 26. Rello J, Gatell JM, Almirall J, Campistol JM, Gonzalez J, Puig de la Bellacasa J. Evaluation of culture techniques for identification of catheter-related infection in hemodialysis patient. Eur J Clin Microbiol Infect Dis. 1989;8:620–2. 27. Gutierrez J, Leon C, Matamoros R, Nogales C, Martin E. Catheter related bacteraemia and fungaemia. Reliability of two methods for catheter culture. Diagn Microbiol Infect Dis. 1992;15: 575–8. 28. Cercenado E, Ena J, Rodriguez-Creixems M, Romero I, Bouza E. A conservative procedure for the diagnosis of catheter-related infections. Arch Intern Med. 1990;150:1417–20. 29. Rello J, Coll P, Prats G. Laboratory diagnosis of catheter-related bacteraemia. Scand J Infect Dis. 1991;23:583–8. 30. Aufwerber E, Ringertz S, Ransjo U. Routine semiquantitative cultures and central venous catheter-related bacteraemia. APMIS. 1991;99:627–30. 31. Raad II, Sabbagh MF, Rand KH, Sherertz RJ. Quantitative tip culture methods and the diagnosis of central venous catheter-related infections. Diagn Microbiol Infect Dis. 1992;15:13–20. 32. Collignon PJ, Soni N, Pearson IY, Woods WP, Munro R, Sorrell TC. Is semiquantitative culture of central vein catheter tips useful in the diagnosis of catheter-associated bacteraemia? J Clin Microbiol. 1986;24:532–5. 33. Widmer AF, Nettleman M, Flint K, Wenzel RP. The clinical impact of culturing central venous catheters. A prospective study. Arch Intern Med. 1992;152:1299–302. 34. Raad II, Sabbagh MF, Rand KH, Sheretz RJ. Quantitative tip culture methods and the diagnosis of central venous catheter related infections. Diagn Microbiol Infect Dis. 1992;15:13–20. 35. Bouza E, Alvarado N, Alcala L, et al. A prospective, randomized, and comparative study of 3 different methods for the diagnosis of intravascular catheter colonization. Clin Infect Dis. 2005; 40:1096–100. 36. Bjornson HS, Colley R, Bower RH, Duty VP, Schwartz-Fulton JT, Fischer JE. Association between microorganism growth at the catheter insertion site and colonization of the catheter in patients receiving total parenteral nutrition. Surgery. 1982;92: 720–7.

10  Catheter-Related Infections in Cancer Patients 37. Brun-Buisson C, Abrouk F, Legrand P, Huet Y, Larabi S, Rapin M. Diagnosis of central venous catheter-related sepsis. Critical level of quantitative tip culture. Arch Intern Med. 1987;147: 873–7. 38. Sherertz R, Raad I, Belani A, et  al. Three-year experience with sonicated vascular catheter cultures in a clinical microbiology laboratory. J Clin Microbiol. 1990;28:76–82. 39. Cleri DJ, Corrado ML, Seligman SJ. Quantitative culture of intravenous catheters and other intravascular inserts. J Infect Dis. 1980;141:781–6. 40. Brun-Buisson C, Abrouk F, Legrand P, et al. Diagnosis of central venous catheter related sepsis. A prospective study. Arch Intern Med. 1987;147:873–7. 41. Widmer AF, Frei R. Diagnosis of central venous catheter related infection: comparison of the roll plate and sonication technique in 1000 catheters [abstract K-2036]. In: Paper presented at the 43rd annual interscience conference on antimicrobial agents and chemotherapy, Chicago, 14–17 Sept 2003. 42. Pronovost P, Needham D, Berenholtz S, et al. An intervention to decrease catheter-related bloodstream infections in the ICU. N Eng J Med. 2006;355:2725–32. 43. Veenstra DL, Saint S, Saha S, Lumley T, Sullivan SD. Efficacy of antiseptic-impregnated central venous catheters in preventing catheter related bloodstream infection: a meta-analysis. JAMA. 1999;281:261–7. 44. Mermel LA. Prevention of intravascular catheter related infections. Ann Intern Med. 2000;132:391–402. Erratum, Ann Inter Med 2000;133:5. 45. Widmer AF, Frei R. Diagnosis of central-venous catheter-related infection: comparison of the roll-plate and sonication technique in 1000 catheters [abstract K-2036]. In: 43rd annual interscience conference on antimicrobial agents chemotherapy, Chicago, 14–17 Sept 2003. 46. Spencer RC, Kristinsson KG. Failure to diagnose intravascular associated infection by direct Gram staining of catheter segments. J Hosp Infect. 1986;7:305–6. 47. Crnich CJ, Maki DG. The promise of novel technology for the prevention of intravascular device-related bloodstream infection. I. Pathogenesis and short-term devices. Clin Infect Dis. 2002; 34:1232–42. 48. Maki DG, Ringer M, Alvarado CJ. Prospective randomized trial of povidone-iodine, alcohol, and chlorhexidine for prevention of infection associated with central venous and arterial catheters. Lancet. 1991;338:339–43. 49. Pemberton LB, Ross V, Cuddy P, Kremer H, Fessler T, McGurk E. No difference in catheter sepsis between standard and antiseptic central venous catheters: a prospective randomized trial. Ann Intern Med. 1997;127:257–66. 50. Collin GR. Decreasing catheter colonization through the use of an antiseptic-impregnated catheter: a continuous quality improvement project. Chest. 1999;54:868–72. 51. Veenstra DL, Saint S, Sullivan SD. Cost-effectiveness of antisepticimpregnated central venous catheters for the prevention of catheterrelated bloodstream infection. JAMA. 1999;282(6):554–60. 52. Brun-Buisson C, Doyon F, Sollet JP, Cochard JF, et al. Prevention of intravascular catheter-related infection with newer chlorhexidine-silver sulfadiazine-coated catheters: a randomized controlled trial. Intensive Care Med. 2004;30(5):837–43. 53. Brun-Buisson C, Doyon F, Sollet JP, Cochard JF, Cohen Y, Nitenberg G. Prevention of intravascular catheter-related infection with newer chlorhexidine-silver sulfadiazine-coated catheters: a randomized controlled trial. Intensive Care Med. 2004;30: 837–43. 54. Rupp ME, Lisco SJ, Lipsett PA, et al. Effect of a second-generation venous catheter impregnated with chlorhexidine and silver sulfadiazine on central catheter-related infection. A randomized, controlled trial. Ann Intern Med. 2005;143:570–80.

121 55. Ostendorf T, Meinhold A, Harter C, et  al. Chlorhexidine and silver-sulfadiazine coated central venous catheters in haemato­ logical patients – a double-blind, randomized, prospective, controlled trial. Support Care Cancer. 2005;13:993–1000. 56. Raad I, Darouiche R, Dupuis J, et  al. Central venous catheters coated with minocycline and rifampin for the prevention of catheter-related colonization and bloodstream infections. A randomized, double-blind trial. The Texas Medical Center Catheter Study Group. Ann Intern Med. 1997;127(4):267–74. 57. Hanna H, Benjamin R, Chatzinikolaou I, et al. Long-term silicone central venous catheters impregnated with minocycline and rifampin decrease rates of catheter-related bloodstream infection in cancer patients: a prospective randomized clinical trial. J Clin Oncol. 2004;22(15):3163–71. 58. Darouiche RO, Raad II, Heard SO, Thornby JI, Wenker OC, Gabrielli A, et al. Comparison of two anti-microbial impregnated central venous catheters. N Engl J Med. 1999;340:1–8. 59. Wright F, Heyland D, Drover J, McDonald S, Zoutman D. Antibiotic-coated central lines: Do they work in the critical care settings? Clin Intensive Care. 2001;12(1):21–8. 60. Chatzinikolau I, Hanna H, Graviss L, Chaiban G, Perego C, Arbuckle R, et  al. Clinical experience with minocycline and rifampin-impregnated central venous catheters in bone marrow transplantation recipients: efficacy and low risk of developing staphylococcal resistance. Infect Control Hosp Epidemiol. 2003;24(12):961–3. 61. Sampath LA, Tambe SM, Modak SM. In vitro and in vivo efficacy of catheters impregnated with antiseptics or antibiotics: evaluation of the risk of bacterial resistance to the antimicrobials in the catheters. Infect Control Hosp Epidemiol. 2001;22(10): 640–6. 62. Munson El, Heard SO, Doern GV. In vitro exposure of bacteria to antimicrobial impregnated-central venous catheters doesn’t not directly lead to the emergence of antimicrobial resistance. Chest. 2004;126:1628–35. 63. Raad I, Darouiche R, Dupis J, Abi-Said D, Gabrielli A, Hachem R, et  al. Central venous catheters coated with minocycline and rifampin for the prevention of catheter related colonization and bloodstream infections. A randomized, Double Blind Trial. Ann Intern Med. 1997;127:267–74. 64. Raad I. Zero tolerance for catheter-related bloodstream infections: the unnegotiable objective. Infect Control Hosp Epidemiol. 2008;29:952–3. 65. Randolph AG, Cook DJ, Gonzales CA, Andrew M. Benefit of heparin in central venous and pulmonary artery catheters: ­meta-analysis of randomized controlled trials. Chest. 1998; 113:165–71. 66. Shanks RM, Donegan NP, Graber ML, et al. Heparin stimulates Staphylococcus aureus biofilm formation. Infect Immun. 2005;73:4596–606. 67. Henrickson KJ, Axtell RA, Hoover SM, et al. Prevention of central venous catheter-related infections and thrombotic events in immunocompromised children by the use of vancomycin/ ciprofloxacin/ heparin flush solution: a randomized, multicenter, double-blind trial. J Clin Oncol. 2000;18:1269–78. 68. Garland JS, Henrickson KJ, Maki DG. A prospective randomized trial of vancomycin-heparin lock for prevention of catheter-related bloodstream infection in an NNICU [abstract 1734]. In: 2002 annual meeting of the Pediatric Academic Societies, Baltimore, 4–7 May 2002. 69. Rackoff WR, Weiman M, Jacobowski D, et al. A randomized, controlled trial of the efficacy of a heparin and vancomycin solution in preventing central venous catheter infections in children. J Pediatr. 1995;127:147–51. 70. Daghistani D, Horn M, Rodriguez Z, Schoenike S, Toledano S. Prevention of indwelling central venous catheter sepsis. Med Pediatr Oncol. 1996;26:405–8.

122 71. Dogra GK, Herson H, Hutchison B, et al. Prevention of tunneled hemodialysis catheter-related infections using catheter-restricted filling with gentamicin and citrate: a randomized controlled study. J Am Soc Nephrol. 2002;13:2133–9. 72. Bleyer AJ, Mason L, Russell G, Raad II, Sherertz RJ. A randomized, controlled trial of a new vascular catheter flush solution (minocycline-EDTA) in temporary hemodialysis access. Infect Control Hosp Epidemiol. 2005;26:520–4. 73. Raad I, Hanna H, Jiang Y, et al. Comparative activities of daptomycin, linezolid, and tigecycline against catheter-related methicillin-resistant Staphylococcus bacteremic isolates embedded in biofilm. Antimicrob Agents Chemother. 2007;51:1656–60. 74. Raad I, Chatzinikolaou I, Chaiban G, et  al. In vitro and ex vivo activity of minocycline and EDTA against microorganisms embedded in biofilm on catheter surfaces. Antimicrob Agents Chemother. 2003;47:3580–5. 75. Raad I, Buzaid A, Rhyne J, Hachem R, Darouiche R, Safar H, et al. Minocycline and ethlenediaminetetraacetate for the prevention of recurrent vascular catheter infections. Clin Infect Dis. 1997;25:149–51. 76. Christensen GD, Bison AL, Parisi JT, et al. Nosocomial septicemia due to multiply antibiotic-resistant staphylococcus epidermis. Ann Intern Med. 1982;96:1–10. 77. Sattler FR, Foderaro JB, Aber RC. Staphylococcus epidermis bacteremia associated with vascular catheter: an important cause of febrile morbidity in hospitalized patients. Infect Control. 1984;5: 279–83. 78. Engelhard D, Elishoov H, Strauss N, et  al. Nosocomial coagulase negative staphylococcal infections in bone marrow transplantation recipients with central vein catheter. Transplantation. 1996;61:430–4. 79. Fowler VG, Sanders LL, Sexton DJ, et  al. Outcome of Staphylococcus aureus bacteraemia according to compliance with recommendations of infectious disease specialists: experience with 244 patients. Clin Infect Dis. 1998;27:478–86. 80. Ghanem GA, Boktour M, Warneke C, et  al. Catheter-related Staphylococcus aureus bacteremia in cancer patients: high rate of complications with therapeutic implications. Medicine. 2007;86:54–60. 81. Abdelkefi A, Ben Romdhane N, Kriaa A, et  al. Prevalence of inherited prothrombotic abnormalities and central venous catheter-related thrombosis in haematopoietic stem cell transplants recipients. Bone Marrow Transplant. 2006;36:885–9. 82. Fowler Jr VG, Olsen MK, Corey R, et  al. Clinical identifiers of complicated Staphylococcus aureus bacteraemia. Arch Intern Med. 2003;163:2066–71. 83. Raad I, Darouiche R, Vazquez J, et  al. Efficacy and safety of weekly dalbavancin in the treatment of catheter-related bloodstream infections due to Gram-positive pathogens. Clin Infect Dis. 2005;40:374–8. 84. Carpenter CF, Chambers HF. Daptomycin: another novel agent for treating infection due to drug-resistant Gram-positive pathogens. Clin Infect Dis. 2004;38:994–1000. 85. Malanoski GJ, Samore MH, Pefanis A, Karchmer AW. Staphylococcus aureus catheter-associated bacteremia. Minimal effective therapy and unusual infectious complications associated with arterial sheath catheters. Arch Intern Med. 1995;155:1161–6. 86. Fowler Jr VG, Justice A, Moore C, et al. Risk factors for hematogenous complications of intravascular catheter-associated Staphylococcus aureus bacteremia. Clin Infect Dis. 2005;40:695–703.

I. Al Wohoush et al. 87. Elting LS, Bodey GP. Septicemia due to Xanthomonas species and non-aeruginosa Pseudomonas species: increasing incidence of catheter-related infections. Medicine. 1990;69:196–206. 88. Hanna H, Afif C, Alakech B, et al. Central venous catheter-related bacteraemia due to Gram-negative bacilli: significance of catheter removal in preventing relapse. Infect Control Hosp Epidemiol. 2004;25:646–9. 89. Chee L, Brown M, Sasadeusz J, MacGregor L, Grigg AP. Gramnegative organisms predominate in Hickman line-related infections in non-neutropenic patients with hematological malignancies. J Infect. 2008;56:227–33. 90. Rodriguez-Creixems M, Alcala L, Munoz P, Cercenado E, Vicente T, Bouza E. Bloodstream infections: evolution and trends in the microbiology workload, incidence, and etiology, 1985–2006. Medicine (Baltimore). 2008;87:234–49. 91. Mermel LA, Farr BM, Sheretz RJ, Raad II, O’Grady N, Harris JAS, et al. Guidelines for the management of intravascular catheter-related infections. Clin Infect Dis. 2001;32:1249–72. 92. Strinden WD, Helgerson RB, Maki DG. Candida septic thrombosis of the great central veins associated with central catheters: clinical features and management. Ann Surg. 1985;202: 653–8. 93. Hanna H, Afif C, Alakech B, Boktour M, Tarrand J, Hachem R, et al. Central venous catheter-related bacteremia due to gram-negative bacilli: significance of catheter-removal in preventing relapse. Infect Control Hosp Epidemiol. 2004;25(8):646–9. 94. Nguyen MH, Peacock Jr JE, Tanner DC, et al. Therapeutic approaches in patients with candidemia: evaluation in a multicenter, prospective observational study. Arch Intern Med. 1995;155:2429–35. 95. Nucci M, Colombo AL, Silveira F, et al. Risk factors for death in patients with candidemia. Infect Control Hosp Epidemiol. 1998;19: 846–50. 96. Hung C-C, Chen Y-C, Chag S-C, Lu K-T, Hsieh W-C. Nosocomial candidemia in a university hospital in Taiwan. J Formas Med Assoc. 1996;95:19–28. 97. Rex JH, Bennett JE, Sugar AM, et al. Intravascular catheter-exchange and duration of candidemia. Clin Infect Dis. 1995;21:995–6. 98. Raad I, Hanna H, Boktour M, Girgawy E, Danawi H, Mardani M, et al. Management of central venous catheters in patients with cancer and candidemia. Clin Infect Dis. 2004;38:1119–27. 99. Mora-Duarte J, Betts R, Rotstein C, et al. Comparison of caspofungin and amphotericin B for invasive candidiasis. N Engl J Med. 2002;347:2020–9. 100. Oudiz RJ, Widlitz A, Beckman XJ, et al. Micrococcus-associated central venous catheter infection in patients with pulmonary arterial hypertension. Chest. 2004;126:90–4. 101. Dziekan G, Hahn A, Thune G, et  al. Methicillin-resistant Staphylococcus aureus in a teaching hospital: investigation of nosocomial transmission using a matched case-control study. J Hosp Infect. 2000;46:263–70. 102. Raad I, Ramos E, Hachem R, et al. The crucial role of catéters in micrococcal bloodstream infections in cancer patients. Infect Control Hosp Epidemiol. 2009;30:83–5. 103. Chaftari AM, Kassis C, El Issa H, Al Wohoush I, Jiang Y, Rangaraj G, et al. Novel approach using antimicrobial catheters to improve the management of central line-associated bloodstream infections in cancer patients. Cancer. 2010 Dec 14. [Epub ahead of print]

Chapter 11

Intravascular Device-Related Infections: Catheter Salvage Strategies and Prevention of Device-Related Infection Nasia Safdar and Dennis G. Maki

Abstract  The use of intravascular devices for ­administration of chemotherapeutic drugs, fluids, blood products, and nutritional support is essential to the care of patients with cancer. Unfortunately, intravascular devices have great potential to produce iatrogenic disease, especially bloodstream infection originating from colonization of the device used for access or from contamination of the infusate administered through the device. Over two thirds of all healthcare-associated bacteremias originate from devices for vascular access. Probably, more than any other healthcare-associated infection, IVDR BSI is eminently preventable. The first step to preserve vascular access is a highly effective institutional program for the prevention of IVDR BSI. In recent years, high-quality research studies have delineated key measures for prevention, such as chlorhexidine (CHG) for cutaneous antisepsis, maximal barrier precautions, antiinfective-impregnated catheters, and the use of a CVC insertion “bundle,” and IVDR BSI rates in the ICU have declined markedly in most hospitals. However, despite adherence to best practices, IVDR BSI continues to pose formidable challenges, especially in patients with cancer. Catheter salvage in the context of established IVDR BSI is particularly challenging, but recent advances such as antibiotic lock technique are now providing previously unavailable options. Keywords  Catheter infection • Bloodstream infection • Prevention • Treatment

Introduction The use of intravascular devices for administration of chemotherapeutic drugs, fluids, blood products, and nutritional support is essential to the care of patients with cancer. N. Safdar (*) Section of Infectious Diseases, Department of Medicine, University of Wisconsin Medical School, MFCB 5221, 1685 Highland Avenue, Madison, WI 53717, USA e-mail: [email protected]

Unfortunately, intravascular devices have great potential to produce iatrogenic disease, especially bloodstream infection (BSI) originating from colonization of the device used for access or from contamination of the infusate administered through the device [1–4]. Over two thirds of all healthcareassociated bacteremias originate from devices for vascular access [5]. Every year more than five million central venous catheters (CVC) are inserted in the United States [6]. More than 250,000 intravascular catheter-related blood stream infections (IVDR BSI) occur annually with an associated mortality of 12–25% [6]. A recent meta-analysis found mortality to be significantly increased in intensive care unit (ICU) patients who had IVDR BSI compared with those without IVDR BSI (OR, 1.96; 95% confidence interval [CI], 1.25–3.09) (Fig.  11.1) [7]. Each episode of IVDR BSI significantly increases hospital length of stay, and the added health-care costs range from $4,000 to $56,000 per episode [8–10]. Probably, more than any other healthcare-associated infection, IVDR BSI is eminently preventable [5, 11–14]. This chapter focuses on catheter salvage in IVDR BSI. The first step to preserve vascular access is a highly effective institutional program for the prevention of IVDR BSI. In recent years, high-quality research studies have delineated key measures for prevention, and IVDR BSI rates in the ICU have declined markedly in most hospitals [12, 15–26]. However, despite adherence to best practices, IVDR BSI continues to pose formidable challenges, especially in patients with cancer. Catheter salvage in the context of established IVDR BSI is particularly challenging, but recent advances are now providing previously unavailable options.

Pathogenesis of IVDR BSI There are two major sources of IVD-related BSI: (1) colonization of the IVD, device-related infection, and (2) contamination of the fluid administered through the device, infusate-related infection [27]. Contaminated infusate is the cause of most epidemic intravascular device-related BSIs

A. Safdar (ed.), Principles and Practice of Cancer Infectious Diseases, Current Clinical Oncology, DOI 10.1007/978-1-60761-644-3_11, © Springer Science+Business Media, LLC 2011

123

124

N. Safdar and D.G. Maki

Fig. 11.1  Attributable mortality of IVDR BSI in critically ill patients. From Siempos et al. [7] with permission

Fig. 11.2  Potential sources of infection of a percutaneous IVD: the contiguous skin flora, contamination of the catheter hub and lumen, contamination of infusate, and hematogenous colonization of the IVD from distant, unrelated sites of infection [174]

[4, 28]; by contrast, catheter-related infections are responsible for most endemic device-related BSIs. Understanding the pathogenesis of IVD-related BSIs is fundamental to devising effective strategies for the prevention and treatment of these infections; however, relatively few published studies have determined the mechanism of IVD-related colonization and infection using sophisticated molecular techniques to prove or disprove potential routes of infection [29–35]. In order for microorganisms to cause catheter-related infection, they must first gain access to the extraluminal or intraluminal surface of the device where they can adhere to and become incorporated into a biofilm that allows sustained colonization and ultimately hematogenous dissemination [36]. Microorganisms gain access to the implanted IVD by one of three mechanisms: skin organisms invade the percutaneous

tract, probably facilitated by capillary action [37], at the time of insertion or in the days following; microorganisms contaminate the catheter hub (and lumen) when the catheter is inserted over a percutaneous guidewire or later manipulated [38]; or organisms are carried hematogenously to the implanted IVD from remote sources of local infection, such as a pneumonia [39] (Fig. 11.2). With short-term IVDs (in place  0.05) [66]. Although these results are promising, a larger trial powered to show equivalence or superiority and provide information on tolerance and effect of the topical agent on resistance patterns of infecting microorganisms is needed to establish the utility of Medihoney for the prevention of IVDR BSIs in patients receiving hemodialysis through cuffed and tunneled CVCs.

Maximal Barrier Precautions The use of maximal barrier precautions, including cap, sterile gown, mask, large sterile drape, and sterile gloves, significantly reduce the rate of IVDR BSIs when used during catheter insertion [6, 67, 68]. In a RCT, Raad et al. compared maximal barrier precautions with limited precautions (e.g., sterile gloves and a small fenestrated drape) and found the CVC-related BSI rate to be 6.3 times higher in the control group (P = 0.06) [67]. The HICPAC Guideline recommends that maximal barrier precautions be used for all central IVD insertions, including PICCs (rating IA) [6].

Insertion Site According to the HICPAC Guideline, the preferred site for insertion of nontunneled CVCs in adult patients is the subclavian vein (rating 1A) [6]. The femoral site has been reported to be associated with higher rates of catheter colonization as well as increased risk of deep vein thrombosis compared to cephalad sites in adults [6, 40, 69–71]. In an RCT with uncuffed CVCs, comparing femoral and subclavian sites, catheters inserted in a femoral site were associated with a higher incidence of infectious complications (19.8 vs. 4.5%; P 2 years posttransplant. While many common infections can be managed through a strategy of conscientious vaccination, there are

567

many other serious infections that specifically afflict ­immunocompromised patient populations and for which effective vaccines do not yet exist. While vaccines that will address some of these infectious conditions are currently in development, it is unlikely that all important oncological infections will ultimately be addressed by a vaccine approach as market-based development strategies are unlikely to target infections with a negligible impact upon immunocompetent populations. For these niche infections, it will be a continuing challenge for physicians and scientists to apply innovative and cost-effective approaches to disease management.

References 1. Sommer AL, Wachel BK, Smith JA. Evaluation of vaccine dosing in patients with solid tumors receiving myelosuppressive chemotherapy. J Oncol Pharm Pract. 2006;12:143–54. 2. Cohen JI. Strategies for herpes zoster vaccination of immunocompromised patients. J Infect Dis. 2008;197 Suppl 2:S237–41. 3. Kunisaki KM, Janoff EN. Influenza in immunosuppressed populations: a review of infection frequency, morbidity, mortality, and vaccine responses. Lancet Infect Dis. 2009;9:493–504. 4. Wilck MB, Baden LR. Vaccination after stem cell transplant: a review of recent developments and implications for current practice. Curr Opin Infect Dis. 2008;21:399–408. 5. Transplant Infections, 3rd edition, Bowden RA, Ljungman P, and Snydman DR, eds. Lippincott, Williams, and Wilkins, Philadelphia; 2010. 6. Chen W, Wahl SM. TGF-beta: the missing link in CD4+CD25+ regulatory T cell-mediated immunosuppression. Cytokine Growth Factor Rev. 2003;14:85–9. 7. Humphries W, Wei J, Sampson JH, Heimberger AB. The role of tregs in glioma-mediated immunosuppression: potential target for intervention. Neurosurg Clin N Am. 2010;21:125–37. 8. Kirkbride KC, Blobe GC. Inhibiting the TGF-beta signalling pathway as a means of cancer immunotherapy. Expert Opin Biol Ther. 2003;3:251–61. 9. Li MO, Flavell RA. TGF-beta: a master of all T cell trades. Cell. 2008;134:392–404. 10. Nagaraj S, Gabrilovich DI. Tumor escape mechanism governed by myeloid-derived suppressor cells. Cancer Res. 2008;68:2561–3. 11. Pan PY, Ma G, Weber KJ, et  al. Immune stimulatory receptor CD40 is required for T-cell suppression and t regulatory cell activation mediated by myeloid-derived suppressor cells in cancer. Cancer Res. 2009;70(1):99–108. 12. Allavena P, Piemonti L, Longoni D, et al. IL-10 prevents the differentiation of monocytes to dendritic cells but promotes their maturation to macrophages. Eur J Immunol. 1998;28:359–69. 13. Beckebaum S, Zhang X, Chen X, et al. Increased levels of interleukin-10 in serum from patients with hepatocellular carcinoma correlate with profound numerical deficiencies and immature phenotype of circulating dendritic cell subsets. Clin Cancer Res. 2004;10:7260–9. 14. Buelens C, Verhasselt V, De GD, et al. Interleukin-10 prevents the generation of dendritic cells from human peripheral blood mononuclear cells cultured with interleukin-4 and granulocyte/macrophagecolony-stimulating factor. Eur J Immunol. 1997;27:756–62. 15. Enk AH, Angeloni VL, Udey MC, Katz SI. Inhibition of Langerhans cell antigen-presenting function by IL-10. A role for IL-10 in induction of tolerance. J Immunol. 1993;151:2390–8.

568 16. Ludewig B, Graf D, Gelderblom HR, et al. Spontaneous apoptosis of dendritic cells is efficiently inhibited by TRAP (CD40-ligand) and TNF-alpha, but strongly enhanced by interleukin-10. Eur J Immunol. 1995;25:1943–50. 17. Menetrier-Caux C, Montmain G, Dieu MC, et al. Inhibition of the differentiation of dendritic cells from CD34(+) progenitors by tumor cells: role of interleukin-6 and macrophage colony-stimulating factor. Blood. 1998;92:4778–91. 18. Park SJ, Nakagawa T, Kitamura H, et  al. IL-6 regulates in  vivo dendritic cell differentiation through STAT3 activation. J Immunol. 2004;173:3844–54. 19. Pinzon-Charry A, Maxwell T, Lopez JA. Dendritic cell dysfunction in cancer: a mechanism for immunosuppression. Immunol Cell Biol. 2005;83:451–61. 20. Ratta M, Fagnoni F, Curti A, et al. Dendritic cells are functionally defective in multiple myeloma: the role of interleukin-6. Blood. 2002;100:230–7. 21. Cohen N, Mouly E, Hamdi H, et al. GILZ expression in human dendritic cells redirects their maturation and prevents antigenspecific T lymphocyte response. Blood. 2006;107:2037–44. 22. Gabrilovich D, Ishida T, Oyama T, et  al. Vascular endothelial growth factor inhibits the development of dendritic cells and dramatically affects the differentiation of multiple hematopoietic lineages in vivo. Blood. 1998;92:4150–66. 23. Gottfried E, Kreutz M, Mackensen A. Tumor-induced modulation of dendritic cell function. Cytokine Growth Factor Rev. 2008;19:65–77. 24. Kusmartsev S, Nefedova Y, Yoder D, Gabrilovich DI. Antigenspecific inhibition of CD8+ T cell response by immature myeloid cells in cancer is mediated by reactive oxygen species. J Immunol. 2004;172:989–99. 25. Lissoni P, Malugani F, Bonfanti A, et  al. Abnormally enhanced blood concentrations of vascular endothelial growth factor (VEGF) in metastatic cancer patients and their relation to circulating dendritic cells, IL-12 and endothelin-1. J Biol Regul Homeost Agents. 2001;15:140–4. 26. Pak AS, Wright MA, Matthews JP, et al. Mechanisms of immune suppression in patients with head and neck cancer: presence of CD34(+) cells which suppress immune functions within cancers that secrete granulocyte-macrophage colony-stimulating factor. Clin Cancer Res. 1995;1:95–103. 27. Saito H, Tsujitani S, Ikeguchi M, Maeta M, Kaibara N. Relationship between the expression of vascular endothelial growth factor and the density of dendritic cells in gastric adenocarcinoma tissue. Br J Cancer. 1998;78:1573–7. 28. Serafini P, Carbley R, Noonan KA, et al. High-dose granulocytemacrophage colony-stimulating factor-producing vaccines impair the immune response through the recruitment of myeloid suppressor cells. Cancer Res. 2004;64:6337–43. 29. Takahashi A, Kono K, Ichihara F, et  al. Vascular endothelial growth factor inhibits maturation of dendritic cells induced by lipopolysaccharide, but not by proinflammatory cytokines. Cancer Immunol Immunother. 2004;53:543–50. 30. Young MR, Wright MA, Lozano Y, et al. Increased recurrence and metastasis in patients whose primary head and neck squamous cell carcinomas secreted granulocyte-macrophage colony-stimulating factor and contained CD34+ natural suppressor cells. Int J Cancer. 1997;74:69–74. 31. Bonham CA, Lu L, Li Y, et al. Nitric oxide production by mouse bone marrow-derived dendritic cells: implications for the regulation of allogeneic T cell responses. Transplantation. 1996;62:1871–7. 32. Della BS, Gennaro M, Vaccari M, et  al. Altered maturation of peripheral blood dendritic cells in patients with breast cancer. Br J Cancer. 2003;89:1463–72.

W. Decker and A. Safdar 33. Kanto T, Kalinski P, Hunter OC, Lotze MT, Amoscato AA. Ceramide mediates tumor-induced dendritic cell apoptosis. J Immunol. 2001;167:3773–84. 34. Peguet-Navarro J, Sportouch M, Popa I, et al. Gangliosides from human melanoma tumors impair dendritic cell differentiation from monocytes and induce their apoptosis. J Immunol. 2003;170:3488–94. 35. Shurin GV, Shurin MR, Bykovskaia S, et  al. Neuroblastomaderived gangliosides inhibit dendritic cell generation and function. Cancer Res. 2001;61:363–9. 36. Sombroek CC, Stam AG, Masterson AJ, et al. Prostanoids play a major role in the primary tumor-induced inhibition of dendritic cell differentiation. J Immunol. 2002;168:4333–43. 37. Yang L, Yamagata N, Yadav R, et al. Cancer-associated immunodeficiency and dendritic cell abnormalities mediated by the prostaglandin EP2 receptor. J Clin Invest. 2003;111:727–35. 38. Yang T, Witham TF, Villa L, et al. Glioma-associated hyaluronan induces apoptosis in dendritic cells via inducible nitric oxide synthase: implications for the use of dendritic cells for therapy of gliomas. Cancer Res. 2002;62:2583–91. 39. Aalamian M, Tourkova IL, Chatta GS, et  al. Inhibition of dendropoiesis by tumor derived and purified prostate specific antigen. J Urol. 2003;170:2026–30. 40. Hiltbold EM, Vlad AM, Ciborowski P, Watkins SC, Finn OJ. The mechanism of unresponsiveness to circulating tumor antigen MUC1 is a block in intracellular sorting and processing by dendritic cells. J Immunol. 2000;165:3730–41. 41. Monti P, Leone BE, Zerbi A, et al. Tumor-derived MUC1 mucins interact with differentiating monocytes and induce IL-10highIL12low regulatory dendritic cell. J Immunol. 2004;172:7341–9. 42. Muller AJ, Prendergast GC. Indoleamine 2, 3-dioxygenase in immune suppression and cancer. Curr Cancer Drug Targets. 2007;7:31–40. 43. Munn DH, Mellor AL. Indoleamine 2, 3-dioxygenase and tumorinduced tolerance. J Clin Invest. 2007;117:1147–54. 44. Bukur J, Seliger B. The role of HLA-G for protection of human renal cell-carcinoma cells from immune-mediated lysis: implications for immunotherapies. Semin Cancer Biol. 2003;13:353–9. 45. Pistoia V, Morandi F, Wang X, Ferrone S. Soluble HLA-G: are they clinically relevant? Semin Cancer Biol. 2007;17:469–79. 46. Hamblin AD, Hamblin TJ. The immunodeficiency of chronic lymphocytic leukaemia. Br Med Bull. 2008;87:49–62. 47. Couch RB, Englund JA, Whimbey E. Respiratory viral infections in immunocompetent and immunocompromised persons. Am J Med. 1997;102:2–9. 48. Elting LS, Whimbey E, Lo W, et al. Epidemiology of influenza A virus infection in patients with acute or chronic leukemia. Support Care Cancer. 1995;3:198–202. 49. Hassan IA, Chopra R, Swindell R, Mutton KJ. Respiratory viral infections after bone marrow/peripheral stem-cell transplantation: the Christie hospital experience. Bone Marrow Transplant. 2003;32:73–7. 50. Ljungman P. Respiratory virus infections in bone marrow transplant recipients: the European perspective. Am J Med. 1997;102:44–7. 51. Ljungman P. Respiratory virus infections in stem cell transplant patients: the European experience. Biol Blood Marrow Transplant. 2001;7(Suppl):5S–7. 52. Machado CM, Boas LS, Mendes AV, et  al. Low mortality rates related to respiratory virus infections after bone marrow transplantation. Bone Marrow Transplant. 2003;31:695–700. 53. Nichols WG, Guthrie KA, Corey L, Boeckh M. Influenza infections after hematopoietic stem cell transplantation: risk factors, mortality, and the effect of antiviral therapy. Clin Infect Dis. 2004;39:1300–6.

50  Prophylactic Vaccination of Cancer Patients and Hematopoietic Stem Cell Transplant Recipients 54. Schepetiuk S, Papanaoum K, Qiao M. Spread of influenza A virus infection in hospitalised patients with cancer. Aust NZ J Med. 1998;28:475–6. 55. Whimbey E, Elting LS, Couch RB, et al. Influenza A virus infections among hospitalized adult bone marrow transplant recipients. Bone Marrow Transplant. 1994;13:437–40. 56. Yousuf HM, Englund J, Couch R, et al. Influenza among hospitalized adults with leukemia. Clin Infect Dis. 1997;24:1095–9. 57. Chemaly RF, Ghosh S, Bodey GP, et al. Respiratory viral infections in adults with hematologic malignancies and human stem cell transplantation recipients: a retrospective study at a major cancer center. Medicine (Baltimore). 2006;85:278–87. 58. Anderson H, Petrie K, Berrisford C, et  al. Seroconversion after influenza vaccination in patients with lung cancer. Br J Cancer. 1999;80:219–20. 59. Brydak LB, Guzy J, Starzyk J, Machala M, Gozdz SS. Humoral immune response after vaccination against influenza in patients with breast cancer. Support Care Cancer. 2001;9:65–8. 60. Ganz PA, Shanley JD, Cherry JD. Responses of patients with neoplastic diseases to influenza virus vaccine. Cancer. 1978;42:2244–7. 61. Nordoy T, Aaberge IS, Husebekk A, et al. Cancer patients undergoing chemotherapy show adequate serological response to vaccinations against influenza virus and Streptococcus pneumoniae. Med Oncol. 2002;19:71–8. 62. Ortbals DW, Liebhaber H, Presant CA, Van III AA, Lee JY. Influenza immunization of adult patients with malignant diseases. Ann Intern Med. 1977;87:552–7. 63. Chisholm J, Howe K, Taj M, Zambon M. Influenza immunisation in children with solid tumours. Eur J Cancer. 2005;41:2280–7. 64. Chisholm JC, Devine T, Charlett A, Pinkerton CR, Zambon M. Response to influenza immunisation during treatment for cancer. Arch Dis Child. 2001;84:496–500. 65. Gross PA, Lee H, Wolff JA, et  al. Influenza immunization in immunosuppressed children. J Pediatr. 1978;92:30–5. 66. Lange B, Shapiro SA, Waldman MT, Proctor E, Arbeter A. Antibody responses to influenza immunization of children with acute lymphoblastic leukemia. J Infect Dis. 1979;140:402–6. 67. Engelhard D, Nagler A, Hardan I, et al. Antibody response to a two-dose regimen of influenza vaccine in allogeneic T celldepleted and autologous BMT recipients. Bone Marrow Transplant. 1993;11:1–5. 68. Gandhi MK, Egner W, Sizer L, et al. Antibody responses to vaccinations given within the first two years after transplant are similar between autologous peripheral blood stem cell and bone marrow transplant recipients. Bone Marrow Transplant. 2001;28:775–81. 69. Hodges GR, Davis JW, Lewis Jr HD, et al. Response to influenza A vaccine among high-risk patients. South Med J. 1979;72:29–32. 70. Robertson JD, Nagesh K, Jowitt SN, et al. Immunogenicity of vaccination against influenza, Streptococcus pneumoniae and Haemophilus influenzae type B in patients with multiple myeloma. Br J Cancer. 2000;82:1261–5. 71. Schafer AI, Churchill WH, Ames P, Weinstein L. The influence of chemotherapy on response of patients with hematologic malignancies to influenza vaccine. Cancer. 1979;43:25–30. 72. Safdar A, Rodriguez MA, Fayad LE, et al. Dose-related safety and immunogenicity of baculovirus-expressed trivalent influenza vaccine: a double-blind, controlled trial in adult patients with nonHodgkin B cell lymphoma. J Infect Dis. 2006;194:1394–7. 73. Grant RM, Weitzman SS, Sherman CG, et al. Fulminant disseminated Varicella Zoster virus infection without skin involvement. J Clin Virol. 2002;24:7–12. 74. Stratman E. Visceral zoster as the presenting feature of disseminated herpes zoster. J Am Acad Dermatol. 2002;46:771–4.

569

75. Tauro S, Toh V, Osman H, Mahendra P. Varicella zoster meningoencephalitis following treatment for dermatomal zoster in an alloBMT patient. Bone Marrow Transplant. 2000;26:795–6. 76. Redman RL, Nader S, Zerboni L, et  al. Early reconstitution of immunity and decreased severity of herpes zoster in bone marrow transplant recipients immunized with inactivated varicella vaccine. J Infect Dis. 1997;176:578–85. 77. Hata A, Asanuma H, Rinki M, et al. Use of an inactivated varicella vaccine in recipients of hematopoietic-cell transplants. N Engl J Med. 2002;347:26–34. 78. Molrine DC, George S, Tarbell N, et  al. Antibody responses to polysaccharide and polysaccharide-conjugate vaccines after treatment of Hodgkin disease. Ann Intern Med. 1995;123:828–34. 79. Levine AM, Overturf GD, Field RF, et  al. Use and efficacy of pneumococcal vaccine in patients with Hodgkin disease. Blood. 1979;54:1171–5. 80. Hartkamp A, Mulder AH, Rijkers GT, van Velzen-Blad H, Biesma DH. Antibody responses to pneumococcal and haemophilus vaccinations in patients with B-cell chronic lymphocytic leukaemia. Vaccine. 2001;19:1671–7. 81. Siber GR, Weitzman SA, Aisenberg AC. Antibody response of patients with Hodgkin’s disease to protein and polysaccharide antigens. Rev Infect Dis. 1981;3(Suppl):S144–59. 82. Siber GR, Gorham C, Martin P, Corkery JC, Schiffman G. Antibody response to pretreatment immunization and post-treatment boosting with bacterial polysaccharide vaccines in patients with Hodgkin’s disease. Ann Intern Med. 1986;104:467–75. 83. Engelhard D, Cordonnier C, Shaw PJ, et al. Early and late invasive pneumococcal infection following stem cell transplantation: a European Bone Marrow Transplantation survey. Br J Haematol. 2002;117:444–50. 84. Kulkarni S, Powles R, Treleaven J, et al. Chronic graft versus host disease is associated with long-term risk for pneumococcal infections in recipients of bone marrow transplants. Blood. 2000;95:3683–6. 85. Sheridan JF, Tutschka PJ, Sedmak DD, Copelan EA. Immunoglobulin G subclass deficiency and pneumococcal infection after allogeneic bone marrow transplantation. Blood. 1990;75:1583–6. 86. Ek T, Mellander L, Hahn-Zoric M, Abrahamsson J. Intensive treatment for childhood acute lymphoblastic leukemia reduces immune responses to diphtheria, tetanus, and Haemophilus influenzae type b. J Pediatr Hematol Oncol. 2004;26:727–34. 87. Barra A, Cordonnier C, Preziosi MP, et  al. Immunogenicity of Haemophilus influenzae type b conjugate vaccine in allogeneic bone marrow recipients. J Infect Dis. 1992;166:1021–8. 88. Guinan EC, Molrine DC, Antin JH, et al. Polysaccharide conjugate vaccine responses in bone marrow transplant patients. Transplantation. 1994;57:677–84. 89. Goyal S, Pai SK, Kelkar R, Advani SH. Hepatitis B vaccination in acute lymphoblastic leukemia. Leuk Res. 1998;22:193–5. 90. Locasciulli A, Santamaria M, Masera G, et al. Hepatitis B virus markers in children with acute leukemia: the effect of chemotherapy. J Med Virol. 1985;15:29–33. 91. Rosen HR, Stierer M, Wolf HM, Eibl MM. Impaired primary antibody responses after vaccination against hepatitis B in patients with breast cancer. Breast Cancer Res Treat. 1992;23:233–40. 92. Somjee S, Pai S, Kelkar R, Advani S. Hepatitis B vaccination in children with acute lymphoblastic leukemia: results of an intensified immunization schedule. Leuk Res. 1999;23:365–7. 93. Somjee S, Pai S, Parikh P, et al. Passive active prophylaxis against Hepatitis B in children with acute lymphoblastic leukemia. Leuk Res. 2002;26:989–92. 94. Weitberg AB, Weitzman SA, Watkins E, et al. Immunogenicity of hepatitis B vaccine in oncology patients receiving chemotherapy. J Clin Oncol. 1985;3:718–22.

570 95. Yetgin S, Tunc B, Koc A, et al. Two booster dose hepatitis B virus vaccination in patients with leukemia. Leuk Res. 2001;25:647–9. 96. Hovi L, Valle M, Siimes MA, Jalanko H, Saarinen UM. Impaired response to hepatitis B vaccine in children receiving anticancer chemotherapy. Pediatr Infect Dis J. 1995;14:931–5. 97. Zignol M, Peracchi M, Tridello G, et al. Assessment of humoral immunity to poliomyelitis, tetanus, hepatitis B, measles, rubella, and mumps in children after chemotherapy. Cancer. 2004;101:635–41. 98. Jaffe D, Papadopoulos EB, Young JW, et al. Immunogenicity of recombinant hepatitis B vaccine (rHBV) in recipients of unrelated or related allogeneic hematopoietic cell (HC) transplants. Blood. 2006;108:2470–5. 99. Ljungman P, Aschan J, Gustafsson B, et al. Long-term immunity to poliovirus after vaccination of allogeneic stem cell transplant recipients. Bone Marrow Transplant. 2004;34:1067–9. 100. Bosu SK, Ciudad H, Sinks LF, Ogra PI. Antibody response to poliovirus immunization in childhood leukemia. Med Pediatr Oncol. 1975;1:217–25. 101. Florax A, Ehlert K, Becker K, Vormoor J, Groll AH. Bordetella pertussis respiratory infection following hematopoietic stem cell transplantation: time for universal vaccination? Bone Marrow Transplant. 2006;38:639–40. 102. Kochethu G, Clark FJ, Craddock CF. Pertussis: should we vaccinate post transplant? Bone Marrow Transplant. 2006;37:793–4. 103. Suzuki N, Mizue N, Hori T, et al. Pertussis in adolescence after unrelated cord blood transplantation. Bone Marrow Transplant. 2003;32:967. 104. Ljungman P, Fridell E, Lonnqvist B, et al. Efficacy and safety of vaccination of marrow transplant recipients with a live attenuated measles, mumps, and rubella vaccine. J Infect Dis. 1989;159:610–5. 105. Ljungman P, Engelhard D, de la Cámara R, et al. Vaccination of stem cell transplant recipients: recommendations of the Infectious Diseases Working Party of the EBMT. Bone Marrow Transplant. 2005;35:737–46. 106. Machado CM, de Souza VA, Sumita LM, et al. Early measles vaccination in bone marrow transplant recipients. Bone Marrow Transplant. 2005;35:787–91. 107. Griffiths PD. CMV vaccine trial endpoints. J Clin Virol. 2009;46 Suppl 4:S64–7. 108. Schleiss MR. Cytomegalovirus vaccines: at last, a major step forward. Herpes. 2009;15:44–5. 109. Dekker CL, Arvin AM. One step closer to a CMV vaccine. N Engl J Med. 2009;360:1250–2. 110. Pass RF, Zhang C, Evans A, et al. Vaccine prevention of maternal cytomegalovirus infection. N Engl J Med. 2009;360:1191–9. 111. Lockey TD, Zhan X, Surman S, Sample CE, Hurwitz JL. Epstein– Barr virus vaccine development: a lytic and latent protein cocktail. Front Biosci. 2008;13:5916–27. 112. Moutschen M, Leonard P, Sokal EM, et  al. Phase I/II studies to evaluate safety and immunogenicity of a recombinant gp350 Epstein–Barr virus vaccine in healthy adults. Vaccine. 2007;25:4697–705. 113. Sokal EM, Hoppenbrouwers K, Vandermeulen C, et  al. Recombinant gp350 vaccine for infectious mononucleosis: a phase 2, randomized, double-blind, placebo-controlled trial to evaluate the safety, immunogenicity, and efficacy of an Epstein–Barr virus vaccine in healthy young adults. J Infect Dis. 2007;196:1749–53. 114. Bowden RA. Respiratory virus infections after marrow transplant: the Fred Hutchinson Cancer Research Center experience. Am J Med. 1997;102:27–30. 115. Champlin RE, Whimbey E. Community respiratory virus infections in bone marrow transplant recipients: the M.D. Anderson Cancer Center experience. Biol Blood Marrow Transplant. 2001;7(Suppl):8S–10.

W. Decker and A. Safdar 116. Ghosh S, Champlin RE, Englund J, et al. Respiratory syncytial virus upper respiratory tract illnesses in adult blood and marrow transplant recipients: combination therapy with aerosolized ribavirin and intravenous immunoglobulin. Bone Marrow Transplant. 2000;25:751–5. 117. Ljungman P, Ward KN, Crooks BN, et al. Respiratory virus infections after stem cell transplantation: a prospective study from the Infectious Diseases Working Party of the European Group for Blood and Marrow Transplantation. Bone Marrow Transplant. 2001;28:479–84. 118. Nichols WG, Gooley T, Boeckh M. Community-acquired respiratory syncytial virus and parainfluenza virus infections after hematopoietic stem cell transplantation: the Fred Hutchinson Cancer Research Center experience. Biol Blood Marrow Transplant. 2001;7(Suppl):11S–5. 119. Nichols WG, Corey L, Gooley T, Davis C, Boeckh M. Parainfluenza virus infections after hematopoietic stem cell transplantation: risk factors, response to antiviral therapy, and effect on transplant outcome. Blood. 2001;98:573–8. 120. Whimbey E, Champlin RE, Couch RB, et al. Community respiratory virus infections among hospitalized adult bone marrow transplant recipients. Clin Infect Dis. 1996;22:778–82. 121. Whimbey E, Englund JA, Couch RB. Community respiratory virus infections in immunocompromised patients with cancer. Am J Med. 1997;102:10–8. 122. Schickli JH, Dubovsky F, Tang RS. Challenges in developing a pediatric RSV vaccine. Hum Vaccin. 2009;5:582–91. 123. Sato M, Wright PF. Current status of vaccines for parainfluenza virus infections. Pediatr Infect Dis J. 2008;27:S123–5. 124. Flomenberg P, Babbitt J, Drobyski WR, et al. Increasing incidence of adenovirus disease in bone marrow transplant recipients. J Infect Dis. 1994;169:775–81. 125. Howard DS, Phillips II GL, Reece DE, et al. Adenovirus infections in hematopoietic stem cell transplant recipients. Clin Infect Dis. 1999;29:1494–501. 126. La Rosa AM, Champlin RE, Mirza N, et al. Adenovirus infections in adult recipients of blood and marrow transplants. Clin Infect Dis. 2001;32:871–6. 127. Shields AF, Hackman RC, Fife KH, Corey L, Meyers JD. Adenovirus infections in patients undergoing bone-marrow transplantation. N Engl J Med. 1985;312:529–33. 128. Wasserman R, August CS, Plotkin SA. Viral infections in pediatric bone marrow transplant patients. Pediatr Infect Dis J. 1988;7:109–15. 129. Yolken RH, Bishop CA, Townsend TR, et al. Infectious gastroenteritis in bone-marrow-transplant recipients. N Engl J Med. 1982;306:1010–2. 130. Anaissie EJ, Kontoyiannis DP, O’Brien S, et  al. Infections in patients with chronic lymphocytic leukemia treated with fludarabine. Ann Intern Med. 1998;129:559–66. 131. Bodey GP, Mardani M, Hanna HA, et  al. The epidemiology of Candida glabrata and Candida albicans fungemia in immunocompromised patients with cancer. Am J Med. 2002;112:380–5. 132. Edwards Jr JE, Bodey GP, Bowden RA, et al. International conference for the development of a consensus on the management and prevention of severe Candidal infections. Clin Infect Dis. 1997;25:43–59. 133. Viscoli C, Girmenia C, Marinus A, et  al. Candidemia in cancer patients: a prospective, multicenter surveillance study by the Invasive Fungal Infection Group (IFIG) of the European Organization for Research and Treatment of Cancer (EORTC). Clin Infect Dis. 1999;28:1071–9. 134. Baddley JW, Stroud TP, Salzman D, Pappas PG. Invasive mold infections in allogeneic bone marrow transplant recipients. Clin Infect Dis. 2001;32:1319–24. 135. Berenguer J, Rodriguez-Tudela JL, Richard C, et al. Deep infections caused by Scedosporium prolificans. A report on 16 cases in

50  Prophylactic Vaccination of Cancer Patients and Hematopoietic Stem Cell Transplant Recipients Spain and a review of the literature. Scedosporium Prolificans Spanish Study Group. Medicine (Baltimore). 1997;76:256–65. 136. Boutati EI, Anaissie EJ. Fusarium, a significant emerging pathogen in patients with hematologic malignancy: ten years’ experience at a cancer center and implications for management. Blood. 1997;90:999–1008. 137. Maertens J, Lagrou K, Deweerdt H, et al. Disseminated infection by Scedosporium prolificans: an emerging fatality among

571

h­ aematology patients. Case report and review. Ann Hematol. 2000;79:340–4. 138. Musa MO, Al EA, Halim M, et al. The spectrum of Fusarium infection in immunocompromised patients with haematological malignancies and in non-immunocompromised patients: a single institution experience over 10 years. Br J Haematol. 2000;108:544–8. 139. Ito JI, Lyons JM, az-Arevalo D, Hong TB, Kalkum M. Vaccine progress. Med Mycol. 2009;47 Suppl 1:S394–400.

Index

A Abdominal infections, 12 Acanthamoeba spp., 477 Acinetobacter baumannii, 427–428, 491 Acneiform eruptions, 240 Acne keloidalis, 251 Acute generalized exanthematous pustulosis (AGEP), 238 Acute myeloid leukemia (AML), 525 gemtuzumab ozogamicin, 57 invasive mold infections, 264–265 Acyclovir antiviral resistance, HSV, 398 varicella-zoster virus, 399–400 VZV, 362–364 Adaptive immunity, CMV, 341–342 Adenovirus clinical presentation, 377 diagnosis, 378 HSCT recipients, 377–378 immunocompromised patients, 377–378 leukemia patients, 377–378 prevention/vaccination, 378 solid organ transplant patients, 378 treatment, 378 Adoptive immunotherapy, CMV, 350–351 Aerobic gram-negative bacilli definition, 423–424 enterobacteriaceae Escherichia coli, 424–426 Klebsiella pneumoniae, 426 Klebsiella species, 425 magnetic resonance imaging, 425 Serratia marcescens, 425 spectrum of infections, 425 nonfermentative Acinetobacter baumannii, 427–428 antimicrobial stewardship, 429–430 Chryseobacterium species, 428 documented infections therapy, 429 empiric therapy, 429 frequency of infections, 426 moderate-to-high-grade bacteremia frequency, 427 Pseudomonas aeruginosa, 426–427 Pseudomonas fluorescens, 428 Stenotrophomonas maltophilia, 427 treatment, 428 trimethoprim/sulfamethoxazole (TMP/SMX), 427 proportions, 424 Airway mucus impaction, 162–163 Alanine aminotransferase (ALT), HBV and HCV reactivation, 190, 191

Alemtuzumab, 457 CLL, phase III clinical trials in, 55, 56 CMV reactivation, 55–56 prophylaxis, 56 viral infections, 56 Allogeneic hematopoietic stem cell transplant (aHSCT) early posttransplant period antimicrobial therapy in, 19–20 diagnostic procedures, 18–19 fungal infections, 20 neutropenia, epidemiology of infections, 17–18 pulmonary infections and noninfectious complications, 19 fever and infection, 17, 18 intermediate posttransplant period bacterial and fungal infections, 21 epidemiology of infections, 21 late posttransplant period, epidemiology of infections, 22 viral infections early, 20–21 late, 22 Aminoglycosides, drug class, 451 Amphotericin B (AMB), 285 antimicrobial prophylaxis, 536 deoxycholate (dAMB), 307 lipid complex (ABLC), 307, 308 Anaerobic gram-negative bacilli, 430 Angiogenin 4, 177 Anidulafungin, 323, 324 Antibacterial distribution antimicrobial agents, impact of cancer beta-lactams, 445 breakpoints, 444–445 cachexia, 445–446 hypoproteinemia, 446 impairment of organs, 444 neutropenia and neutropenic fever, 445 protein binding, 446 surgery, 445 drug–drug interactions drug absorption affection, 449 drug class, 450–452 drug metabolism and transporters, 449–450 polypharmacy, 448 potential drug interaction management, 448 principles, 448–449 therapeutic management, 447–448 malignant effusions, 447 pharmacokinetic/pharmacokodynamic (PK/PD) indices, 444 pharmacokinetics, 443–444 tissue infections, 446–447

A. Safdar (ed.), Principles and Practice of Cancer Infectious Diseases, Current Clinical Oncology, DOI 10.1007/978-1-60761-644-3, © Springer Science+Business Media, LLC 2011

573

574 Antibacterial prophylaxis, 534–535 neutropenic patients antibiotic prophylaxis, 522–523 high risks patients, 522 infection, 521–522 myeloid growth factors, 523 parameters affected, 522 prevention strategies, 522, 523 treatment, 523 nonneutropenic patients chronic graft versus host disease (GVHD), 524 impaired humoral immunity, 523 splenectomy, 524 Antibiotic-coated catheter, 117–118 Antibiotics cycling antimicrobial resistance, 512–513 ASP, 501–502 neutropenic patient prophylaxis, antibacterial, 522–523 therapy, 7–8 Anti-CD2 antibodies, 58 Anti-CD3 antibodies, 58 Anti-CD4 antibodies, 57–58 Anti-CD20 antibodies radioimmunoconjugates, 54 rituximab, 48–54 second-generation, 54, 55 Anti-CD22 antibodies, 57 Anti-CD23 antibodies, 57 Anti-CD33 antibodies, 57 Anti-CD52 antibodies, 54–56 Antifungal drug resistance anidulafungin, 323, 324 breakthrough infections, 324 caspofungin, 323–325 echinocandin drugs, 323 resistance, 324 elevated MICs, 325 Erg11, 318 Fks mediated resistance, 325 mutations, 324 non-Fks mechanisms, 325 fungal susceptibility, 318–320, 323 glucan synthase, 323–325 invasive fungal infections, 317 itraconazole, 322 mechanisms, 318, 320 micafungin, 323, 324 minimal inhibitory concentration (MIC), 324 newer triazole antifungals CYP51p, 318, 320 systemic, 318, 319 pharmacokinetic variability posaconazole, 322–323 voriconazole, 320–322 in vitro susceptibilities, 324 Antifungal prophylaxis, 535–536 antimold prophylaxis, 527 Candida krusei, 524–525 neutropenic patients acute myeloid leukemia (AML), 525 Aspergillus, primary, 525–526 candidiasis, primary, 524–525

Index chemotherapy regimens, duration of, 524 fluconazole, 524–525 invasive fungal infections (IFI), 524 posaconazole, 525 risk assessment, 524 secondary prophylaxis, 526 nonneutropenic patients, 526–527 Antifungal susceptibility testing, in vitro Aspergillus species Aspergillus fumigatus, 305–306 Aspergillus terreus, 306 echinocandins, 306 MIC distributions, 305, 306 resistance mechanisms, 306 Candida species amphotericin B (AMB), 305 Candida krusei, 304 CLSI standardized method, 305 drugs, 305 fluconazole treatment, 304 MIC interpretative criteria, 304 moulds, 305 non-Aspergillus moulds, 307 Antifungal therapies. See also Antifungal drug resistance cryptococcal disease, 294–295 histoplasmosis, 298 invasive aspergillosis (IA) clinical data, 311–312 clinical trials, 309, 310 preclinical data, 309, 311 Antiinfective-impregnated catheters, catheter salvage, 129 Antiinfective lock solutions, catheter salvage, 129–130 Antiinfective lock therapy (ALT), catheter salvage adjunctive treatment, studies of, 133 concentrations of, 134 Antiinfective luer-activated devices, catheter salvage, 130 Anti-interleukin–2 receptor antibodies, hematologic malignancies basiliximab, 59 daclizumab, 58–59 denileukin diftitox, 58 Anti-interleukin–6-receptor antibodies, hematologic malignancies, 59 Antimicrobial prophylaxis amphotericin B, 536 Aspergillus species, 535, 538 Candida infections, 535, 538 caspofungin, 536 clinical trials antibacterial prophylaxis, 534–535 antifungal prophylaxis, 535–536 guidelines, neutropenic patients, 537–538 considerations, 536–537 drugs role, 538 fatal infections, 537 fungal infections, 535, 537 gram-negative sepsis, 537 life-threatening infection, 533 micafungin, 536 neutropenia, 538 Antimicrobial resistance ASP Clostridium difficile associated diarrhea (CDAD), 501 febrile neutropenia, 499–500 Klebsiella pneumoniae carbapenemases (KPC), 500 vancomycin resistant enterococci, 500 prevention antibiotic cycling, 512–513

Index carbapenemases, 508 CDC, 510–512 Enterobacteriaceae, 508 Enterococcus faecium, 507–508 gram-negative organisms, 508 gram-positive bacteria infections, 507 hospitalized patients, 510, 511 infection control strategies, 510–512 Listeria monocytogenes, 514 mathematical models, antibiotic resistance, 509–510 methicillin-resistant Staphylococcus aureus (MRSA), 507 multiresistant bacterial organisms, 507, 508 nanograms, 514 narrow spectrum, 513–514 organisms, 507 phage-based therapy, 514 search and destroy approach, 510 shorter antibiotic courses, 513–514 strategies, 509–510 treatment, 512–514 Antimicrobials agents, impact of cancer beta-lactams, 445 breakpoints, 444–445 cachexia, 445–446 hypoproteinemia, 446 impairment of organs, 444 neutropenia and neutropenic fever, 445 protein binding, 446 surgery, 445 coating, of catheters, 116 peptides, 177–178 therapy, aHSCT duration of, 20 neutropenic fever, 19–20 Antimicrobial stewardship neutropenia, 101, 102 NFGNB, 429–430 Antimicrobial stewardship program (ASP) Acinetobacter baumannii, 491 antibiotic cycling, 501–502 antimicrobial resistance Clostridium difficile associated diarrhea (CDAD), 501 febrile neutropenia, 499–500 Klebsiella pneumoniae carbapenemases (KPC), 500 vancomycin resistant enterococci, 500 barriers and challenges, 494–495 Clostridium difficile infection (CDI), 491 computer-based infrastructure, 492 emerging infections network (EIN), 494–495 fluoroquinolones, 503 gram-negative (GN) organisms, 501 implementation of, 492 infectious diseases (ID), 492 injudicious antimicrobial use, 491 multidisciplinary team, 492–493 outpatient antibiotic therapy, 502–504 postprescribing review, 493–494 Pseudomonas aeruginosa, 501 strategies of, 493–494 streamlining, 494 Antimold prophylaxis, 527 Antimycobacterial immunity, Mycobacterium tuberculosis infection alemtuzumab, 457 biology of, 455–456 bone marrow transplantation, 457

575 cancer therapies, 456–457 pharmacologic cancer therapy, 457 purine analogs, 457–458 risk factors, 456–457 states of susceptibility, 456 temozolamide, 458 TNF inhibitors, 458 Antiparasitic prophylaxis, 528 Antipneumocystis, 528 Antiseptic catheters, 117 Anti-TNFa monoclonal antibodies, hematologic malignancies, 59–60 Antiviral prophylaxis CMV, 346–347 cytomegalovirus (CMV), 527 Epstein-Barr virus (EBV), 527–528 herpes simplex virus (HSV), 527 neutropenic patients, 527 varicella-zoster virus (VZV), 527 VZV, 364–365 Antiviral resistance cytomegalovirus ganciclovir, 400–401 hematopoietic stem cell transplantation, 400 prevention, 401 rheumatoid arthritis, 401 valganciclovir, 400 genotypic resistance, 397, 398 hepatitis B virus lamivudine-resistant mutants, 403 prophylactic and therapeutic strategies, 402 vaccination, 403 herpes simplex virus acyclovir, 398 cidofovir, 399 definition, 397–398 diagnosis, 399 leflunomide, 399 rheumatoid arthritis, 399 risk factors, 398–399 therapy, 399 toxicity, 399 influenza viruses antiviral therapy, 401–402 diagnosis, 402 oseltamivir, 402 zanamivir, 402 varicella-zoster virus, 399–400 Apolizumab (Hu1D10), 60 Arthropod bites, immunocompromised traveler, 555, 556 Aseptic meningitis, 211–212 ASP. See Antimicrobial stewardship program (ASP) Aspergillosis, 9, 257, 258, 287–288. See also Invasive aspergillosis (IA) invasive fungal diseases, 331, 332 Aspergillus, antifungal prophylaxis, 525–526 Aspergillus fumigatus, 150, 283, 305–306 Aspergillus spp. antifungal prophylaxis, 535 Aspergillus fumigatus, 305–306 Aspergillus terreus, 306 echinocandins, 306 infective endocarditis, 228 MIC distributions, 305, 306 neutropenic patients, 538 resistance mechanisms, 306 Autoimmune bullous dermatoses, 236–237

576 B Bacillus Calmette-Guerin (BCG), 43 Bacteremia, 198 Bacterial colonization and host immunity gastrointestinal mucosa and intestinal immune responses adaptive immunity, 178 antimicrobial peptides, 177–178 dendritic cells (DCs), 177 effector compartment, 178 epithelial cells, types of, 176 IgA and cytokines, 178–179 initiation compartment, 178 microbiota, 175–176 Bacterial infections, 7 aHSCT, 21 Bacterial meningitis, acute, 211 Balamuthia mandrillaris, 477 Bartonella henseleae, 484 Basiliximab, 59 Behçet disease (BD), 239, 240 Beta-D-glucan assay, 284 candidiasis, 263 invasive candidiasis, 275 invasive mold infections, 267 Beta-lactam antibiotics, 451 Bevacizumab, colon cancer, 42 BK virus (BKV) definition, 387 hemorrhagic cystitis (HC) associated disease, 388–389 cidofovir, 390 clinical results, 390, 392 definition, 388 diagnosis, 389 HCT recipients, 390 intravenous immunoglobulin (IVIg), 390 leflunomide, 390 nephritis, 392 organ manifestations, 392 treatment, 389–391 transmission and pathogenesis, 388 viremia, 388 virologic aspects, 387–388 Blastomyces dermatitidis, 294, 483 Blastomycosis Blastomyces dermatitidis, 296 clinical symptoms, 296, 297 diagnosis, 296 immunosuppression, 296 Blood cultures, invasive candidiasis, 275 Bone marrow transplantation, 457 Bowel-associated dermatosis-arthritis syndrome, 239 Brain abscess clinical presentation, 213 diagnosis and management of, 213 etiology and risk factors, 212–213 listeriosis, 438 Brain cancer, postoperative infections diagnosis of, 68 etiology of, 68 incidence of, 67–68 prevention, 68 risk factors, 68 treatment of, 68 Brain stem encephalitis, 437–438

Index Breast cancer, 41–42 breast cellulitis, 42 interventions, surgical site infections diagnosis of, 71 etiology of, 71 incidence of, 70 prevention, 71 risk factors, 70–71 treatment of, 71 Bronchial obstruction, pneumonia, 147–148 Bronchiolitis obliterans organizing pneumonia (BOOP), 158, 159 Bronchopleural fistula (BPF), 72 Bullous drug eruptions, 235–236 Bullous graft-versus-host-disease (GVHD), 235 Bullous insect bite reaction, 235 Bullous pemphigoid, 237 C Cachexia, antimicrobial agents, 445–446 Calciphylaxis, 244 Candida infections antifungal prophylaxis, 535 neutropenic patients, 535 Candida krusei, 304, 524–525 Candida spp., 9 amphotericin B (AMB), 305 Candida krusei, 304, 524–525 catheter salvage, 135 CLSI standardized method, 305 CRBSI, 119 drugs, 305 echinocandin drugs, 323 Fks-mediated resistance, 325 fluconazole treatment, 304 infective endocarditis, 227–228 MIC interpretative criteria, 304 Candidemia and acute disseminated candidiasis, 278–279 clinical presentation, 276 Candidiasis, 257 antifungal prophylaxis, 524–525 candidemia, diagnosis of beta-D-glucan assay, 263 microbiology and culture, 262–263 PCR, 263–264 clinical syndromes, 262 disseminated maculopapular skin rash, 262 hepatosplenic, diagnosis of, 264 Capnocytophaga canimorsus, 482 Carbapenemases, antimicrobial resistance, 508 Cardiogenic (hydrostatic) pulmonary edema, 153–154 Caspofungin antifungal drug resistance, 323–325 antimicrobial prophylaxis, 536 Catheter-related blood stream infection (CRBSI) CVCs, 113 diagnosis of, 114 genitourinary tract infections, 199 management of Candida species, 119 CoNS, 118 gram negative bacilli, 119

Index guide wire, exchange, 119–120 Micrococcus species, 119 Staphylococcus aureus, 119 maximal sterile barrier antibiotic-coated catheter, 117–118 antimicrobial coating of, 116 antimicrobial lock solutions, 118 antiseptic catheters, 117 elements, 116 tunneling, 116 pathogenesis, 113 systemic catheter infections, 114 Catheter-related infections, 12–13, 465–466. See also Catheter-related blood stream infection (CRBSI) biofilm, 118 with catheter removal, diagnostic tests comparison of, 115 quantitative segment culture, 116 semiquantitative roll-plate culture, 115 clinical manifestations and definitions, 114 prevention of, 116, 117 without catheter removal, diagnostic tests comparative quantitative blood culture, 114 differential time to positivity, 115 Catheter salvage, IVDR BSI in prevention antiinfective-impregnated catheters, 129 antiinfective lock solutions, 129–130 antiinfective luer-activated devices, 130 catheter securement, 130 chlorhexidine bathing, 129 chlorhexidine-impregnated insertion site dressings, 129 cutaneous antisepsis, 126 HICPAC guidelines, 125, 126 insertion site, 128 institutional systems, 131–132 intensive insulin therapy, 130–131 maximal barrier precautions, 128 simulation-based training, 128 strategies for, 127 topical antimicrobials, 126–128 treatment antiinfective lock therapy, 133–134 Candida spp., 135 CoNS, 136 gram-negative bacilli, 136 guidewire exchange, 134 long-term cuffed and tunneled central venous catheter, 132 pathogen-specific recommendations, 134–135 Staphylococcus aureus, 135–136 urokinase, 134 Cat scratch disease, 484 Cell-mediated immunity, nocardiosis, 439–440 Cellular immune dysfunction, hematologic malignancies, 33, 34 Cellulitis, 201–202 Centers for Disease Control and Prevention (CDC), antimicrobial resistance, 510–512 Central nervous system (CNS) cancer, 43–44 cryptococcal disease, 294 diagnosis, methodical approach, 207–208 histoplasmosis, 298 infectious syndromes and management brain abscess, 212–213 encephalitis, 208–210

577 meningitis, 210–212 postoperative infections, 214 listeriosis, infection, 437 noninfectious problems GVHD, 215 neoplastic meningitis, 214–215 PNS, 215 RPLS, 215 stem cell transplantation (SCT), 207 zygomycete infection, 308 Central venous catheters (CVCs), 79, 113 Chagas’ disease, 477 Chemotherapy Mycobacterium tuberculosis infection, 459–460 and radiation-related genitourinary tract infections bacteremia, 198 catheter-related bloodstream infection, 199 febrile neutropenia, 198–199 Chemotherapy-induced acral blisters and erythema, 248 Chemotherapy-induced lung injury (CILI) diagnosis, 154 drug toxicity, chronic manifestations of, 154 histopathologic changes in, 155 radiographic changes in, 155 steroid therapy, 156 Chest computed tomographic hyperinfection syndrome, 475 computed tomography, 344 radiography, 344 Staphylococcus aureus, CT, 411 Children, postoperative infections age, 78 blood transfusion, 79 CVCs, 79 minimally invasive surgery (MIS), 79 neutropenia, 79 nutrition, 79 type of tumor, 78–79 Chlamydia psittaci, 487 Chlorhexidine, catheter salvage, 129 Chronic lymphocytic leukemia (CLL), 35 Cidofovir antiviral resistance, HSV, 399 BKV, 390 CMV, 348, 350 Ciprofloxacin, 451 Clarithromycin, 451 Clostridial bacteremia, 198 Clostridial myonecrosis, 203 Clostridium difficile associated diarrhea (CDAD), 501 Clostridium difficile infection (CDI), 491 diagnosis, 185 epidemiology and risk factors, 184–185 management, 186 pathogenesis, 185 prevention and control, 186 transplantation, 185 CNS. See Central nervous system (CNS) Coagulase-negative staphylococci (CoNS), 412 catheter salvage, 136 CRBSI, 118 infective endocarditis, 226 Coccidiodes immitis, 295

578 Coccidioidomycosis azole antifungals, 296 Coccidiodes immitis, 295 diagnosis, 296 T-cell immunity, 295 unifocal/multifocal pulmonary disease, 295 Colon cancer, 42, 43 Colony stimulating factors (CSF), 333–334 Coma bullae, 234 Community-acquired pneumonia (CAP), 146 Computed tomography (CT) scan invasive mold infections, 264–265 neutropenic enterocolitis, 183 Congestive heart failure, 153–154 Coronavirus clinical presentation, 380 diagnosis, 381 immunocompromised patients, 380 prevention, 381 treatment, 381 Cowpox virus, 485 Coxiella burnetii, 484 CRBSI. See Catheter-related blood stream infection (CRBSI) C reactive protein (CRP), 107 Critically ill cancer patients critical care utilization diagnostic approach, 88–89 life-threatening complications, 88 scoring systems, 88 therapy, 89 ICU oncologists and infectious disease specialists, 87–88 patient’s goals, 88 infectious complications, prevention of, 90 Cryptococcal disease AIDS epidemic, 293 antifungal therapy, 294–295 cancer patients, 295 central nervous system, 294 clinical findings, 293–295 Cryptococcus neoformans, 293 Cryptococcus species, 294 infections, 293 respiratory mycosis, 294 Cryptococcosis, 9 Cryptococcus neoformans, 293, 485 Cryptococcus species, 294 Cryptogenic organizing pneumonitis (COP), 160–161 Cryptosporidium spp., 478 Cutaneous antisepsis, catheter salvage, 126 Cutaneous T-cell lymphoma, 243 Cytochrome P450 isoenzymes, 449, 450 Cytokines, immunotherapy, 335, 336 Cytomegalovirus (CMV) adoptive immunotherapy, 350–351 antiviral prophylaxis, 527 antiviral resistance, 349–350 ganciclovir, 400–401 hematopoietic stem cell transplantation, 400 prevention, 401 rheumatoid arthritis, 401 valganciclovir, 400 chest computed tomography, 344 chest radiography, 344 cidofovir, 348, 350 clinical manifestations, 344–345

Index diagnosis anti-CMV immunostaining, 343 hematoxylin and eosin (H&E) stain, 343 methods, 342 mRNA detection, 344 quantitative polymerase chain reaction (qPCR), 343 shell vial technique, 343 foscarnet, 348 ganciclovir-resistant, 349–350 host immunity adaptive immunity, 341–342 immune evasion, 342 innate immunity, 342 HSCT, 21 less, 342 management of, 350 natural killer (NK) cells, 342 non-HCT setting, 351 pneumonia, 151, 344 prevention antiviral agents, 347–348 antiviral prophylaxis and pre-emptive therapy, 346–347 immunoprophylaxis, 346 monitoring and pre-emptive therapy, 348 posttransplant risk reduction, 346–347 pretransplant risk reduction, 346 special populations, 348 retinitis, 344–345 risk factors after allogeneic HCT, 345 allogeneic HCT recipients, 345 autologous HCT, 346 nonmyeloablative HCT, 345 umbilical cord blood transplantation, 346 rituximab, 52–53 stem cell transplantation, 346 structure and replication, 341 vaccination, 350 valganciclovir-resistant, 348, 349 D Daclizumab, 58–59 Defensins, 177 Delayed pulmonary toxicity syndrome, 162 Dendritic cells (DCs), 177 Denileukin diftitox, 58 Dermatitis acute, 233 irritant dermatitis, 241, 242 radiation dermatitis, with erythema, 242 Diabetic blisters, 235 Diffuse alveolar damage (DAD), 157 Diffuse alveolar hemorrhage (DAH), 160 Dimorphic fungi, 331, 332 Dipylidium caninum, 484 Dirofilaria immiti, 484 Disseminated candidiasis acute, 278–279 chronic, 279 skin lesions in, 276 Disseminated intravascular coagulation (DIC), 244 Documented infections therapy, 429 Drug–drug interactions cytochrome P450 inhibitor, 449

Index cytochrome P450 isoenzymes, 449, 450 drug absorption affection, 449 drug class aminoglycosides, 451 beta-lactam antibiotics, 451 ciprofloxacin, 451 erythromycin/clarithromycin, 451 linezolid, 451 metronidazole, 451 moxifloxacin, 451 rifamycin derivates, 450 tigecycline, 452 trimethoprim-sulfamethoxazole, 452 vancomycin, 451 drug metabolism and transporters, 449–450 P-glycoprotein, 449 polypharmacy, 448 potential drug interaction management, 448 principles, 448–449 therapeutic management, 447–448 E EBV. See Epstein-Barr virus (EBV) Echinocandins, 278, 279, 285–286 Aspergillus species, 306 drugs, 323 resistance, 324 zygomycosis, 308 Edema and lymphedema bullae, 235 EGFR-induced acneiform pustulosis, 240 Emerging infections network (EIN), 494–495 Empiric therapy antibiotic, 98–100 antifungal, 108–109, 287 antimicrobial, 417 febrile neutropenia, controversies in, 105–109 NFGNB, 429 Encephalitis clinical manifestations of, 208 diagnosis, 209 immunocompetent host, 208, 210 immunosuppressed host, 208–210 parainfectious encephalitides, 208 post-infectious/post-immunization, 209 septic encephalopathy, 209 treatment recommendations, 209–210 Endemic mycosis blastomycosis Blastomyces dermatitidis, 296 clinical symptoms, 296, 297 diagnosis, 296 coccidioidomycosis azole antifungals, 296 Coccidiodes immitis, 295 diagnosis, 296 T-cell immunity, 295 unifocal/multifocal pulmonary disease, 295 histoplasmosis antifungal therapy, 298 central nervous system, 298 clinical findings, 297 culture of, 297 Histoplasma antigen, 297 Histoplasma capsulatum, 297 Endocarditis, 277. See also Infective endocarditis (IE)

579 Endophthalmitis, 276 End-organ infection, 12 Engraftment syndrome (ES), 159 Enteric pathogens, 552, 554–555 Enterobacteriaceae, 508 Escherichia coli, 424–426 Klebsiella pneumoniae, 426 Klebsiella species, 425 magnetic resonance imaging, 425 Serratia marcescens, 425 spectrum of infections, 425 Enterococcus clinical presentation/diagnosis, 416 epidemiology, 416 infective endocarditis, 227 treatment, 416–417 Enterococcus faecium, 507–508 Enterovirus clinical presentation, 381 diagnosis, 381 immunocompromised patients, 381 prevention, 381 treatment, 381 Eosinophilic dermatoses, 249 Eosinophilic folliculitis, 240 Epithelial innate immunity, 168–169 Epstein-Barr virus (EBV) antiviral prophylaxis, 527–528 B cell, 365 immunocompromised hosts, 365–366 transmission, 365 treatment, 366 Erythema annulare centrifugum, 247–248 and chemotherapy-induced acral blisters, 248 gyratum repens, 247–248 multiforme (EM), 246–247 nodosum (EN), 245–246 Erythematous lesions chemotherapy-induced acral blisters and erythema, 248 EM/SJS and TEN, 246–247 eosinophilic dermatoses, 249 erythema annulare centrifugum, 247, 248 erythema gyratum repens, 247–248 granuloma annulare, 248–249 necrolytic migratory erythema, 248 urticaria and angioedema, 246 Erythromycin, 451 Escherichia coli, 424–426 Esophageal cancer, postoperative infections diagnosis of, 73 incidence of, 72 prevention, 73 risk factors, 72–73 treatment of, 73 Esophagitis, invasive candidiasis, 276 Eukaryotic infections, 566–567 F Febrile neutropenia algorithm for, 101 ASP, 499–500 empiric therapy, controversies in, 105 acute phase protein responses, 107 antibiotic regimen, 106

580 Febrile neutropenia (cont.) antifungal therapy, 107–109 cause of, negative blood cultures, 106–107 high risk for, 109 genitourinary tract infections, 198–199 low-risk antibiotic regimens in, 98 outpatient management of, 99 treatment options for, 98 Fks mediated resistance, 325 mutations, 324 non-Fks mechanisms, 325 Fluconazole, antifungal prophylaxis, 524–525 Fluoroquinolones, ASP, 503 Food and drink, infection prevention, 547–548 Foscarnet, CMV, 348 Friction blister, 234 Fungal infections, 8–10, 258. See also Invasive mold infections (IMIs) aHSCT, 20 antifungal susceptibility testing, in vitro Aspergillus species, 305–307 Candida species, 304–305 moulds, 305 non-Aspergillus moulds, 307 antimicrobial prophylaxis, 535, 537 combination antifungal therapy, 309–312 invasive, 317 preemptive therapy, 287 risk factors, 284 invasive aspergillosis (IA) clinical data, 311–312 clinical trials, 309, 310 micafungin (MICA), 311 preclinical data, 309, 311 therapeutic drug monitoring (TDM) parameters, 301, 302 posaconazole, 303–304 voriconazole, 301–303 zygomycosis treatment adjunctive therapy, 309 AMB deoxycholate (dAMB), 307 animal data, 308 antifungal agents, 307 clinical data, 308–309 in vitro data, 308 Fungal susceptibility, antifungal drug resistance, 318–320, 323 Fungi, infective endocarditis Aspergillus species, 227 Candida species, 227–228 Fusariosis, 288 Fusarium spp., 9 G Galactomannan EIA antigen, invasive mold infections, 266–267 test, 284 Ganciclovir antiviral resistance, CMV, 400–401 CMV, 349–350 Gastrointestinal mucosa and intestinal immune responses, bacterial colonization adaptive immunity, 178 antimicrobial peptides, 177–178

Index dendritic cells (DCs), 177 effector compartment, 178 epithelial cells, types of, 176 IgA and cytokines, 178–179 initiation compartment, 178 Gastrointestinal (GI) tract interventions, postoperative infections diagnosis of, 74 etiology of, 74 incidence of, 73 microorganisms, 74 prevention, 74–75 risk factors, 73–74 treatment of, 74 Gemtuzumab ozogamicin, 57 Genital and urinary tract neoplasms, postoperative infections diagnosis of, 76 etiology of, 76 gynecologic procedures, 75 incidence of, 75 prevention, 76–77 risk factors, 75–76 treatment of, 76 vaginal cuff infection, 75 Genitourinary tract infections bowel preparation, 200 chemotherapy and radiation-related bacteremia, 198 catheter-related bloodstream infection, 199 febrile neutropenia, 198–199 factors, 195 fever, noninfectious causes of, 204 implantable device infections, 199 microflora, 195 peritonitis and intraabdominal abscess, 200–201 predisposing risk factors and infections in, 196 septic pelvic thrombophlebitis, 203–204 surgery-related intraabdominal and pelvic abscess, 197–198 wound infection, 197 surgical infection, prevention of, 200 tumor-related, 196 wound infections cellulitis, 201–202 clostridial myonecrosis, 203 necrotizing fasciitis, 202–203 Glucan synthase, 323–325 Graft-versus-host-disease (GVHD) basiliximab, 59 chronic, 524 daclizumab, 58–59 HSCT, 22 Nikolsky sign and epidermal detachment, 235 Gram-negative bacilli aerobic definition, 423–424 enterobacteriaceae, 424–426 nonfermentative, 426–430 proportions, 424 anaerobic, 430 catheter salvage, 136 CRBSI, 119 multi-drug-resistant (MDR), 423 Gram-negative (GN) organisms antimicrobial resistance, 508 ASP, 501 Gram-positive bacteria infections, antimicrobial resistance, 507

Index Gram-positive bacterial disease management invasive bacterial disease, 409, 410 pathogens, 409, 410 staphylococci coagulase negative staphylococci, 412 Staphylococcus aureus, 409–412 streptococci definition, 412–413 empiric antimicrobial therapy, 417 enterococcus, 416–417 b-hemolytic streptococci, 414–415 Streptococcus pneumoniae, 415–416 viridans group streptococci, 413 Granulocyte transfusions, 334–335 Granuloma annulare, 248–249 Grover disease, 241 GU cancers, 43 H Haemophilus influenzae type B (HiB), 564–565 Hair and scalp lesions, 250 Hand hygiene, 546–547 Head and neck cancer interventions, postoperative infections diagnosis of, 69 etiology of, 69 incidence of, 69 prevention, 70 risk factors, 69 treatment of, 69–70 Healthcare Infection Control Practices Advisory Committee (HICPAC) guidelines, 125, 126 Hematologic malignancies acute leukemia, 34–35 cellular immune dysfunction, 33, 34 chronic lymphocytic leukemia, 35 humoral immune dysfunction, 33–34 immune defects in, 34, 35 immune host-defects in host defenses role, patient response, 28 infections control, 28 predominant pathogen association with, 29 lymphoma, 36 monoclonal antineoplastic therapy (see Monoclonal antineoplastic therapy, hematologic malignancies) mucosal impairment, 34 myeloma, 35–36 neutropenia antifungal prophylaxis, 31 bacterial infections, epidemiology of, 30 candidemia, incidence of, 31 disseminated aspergillosis, 32 fungal infections, incidence of, 28, 30 hepatosplenic candidiasis, 29, 31 influenza and mucor pneumonia, 32 MRI of, 30 severe infection episodes, circulating neutrophils, 30 qualitative phagocyte defects, 30–31 splenic dysfunction, 34 Hematopoietic stem cell transplantation (HSCT). See also Allogeneic hematopoietic stem cell transplant (aHSCT) antiviral resistance, CMV, 400 BKV, 387 lung infiltrates, noninfectious complications of early-onset, 159–160 late-onset, 160–162

581 vaccination (see Prophylactic vaccination, HSCT) VZV, 360–362 Hematoxylin and eosin (H&E) stain, 343 b-Hemolytic streptococci clinical manifestations/diagnosis, 414 definition, 414 epidemiology, 414 treatment, 414–415 Hemorrhagic cystitis (HC), BKV associated disease, 388–389 cidofovir, 390 clinical results, 390, 392 definition, 388 diagnosis, 389 HCT recipients, 390 intravenous immunoglobulin (IVIg), 390 leflunomide, 390 nephritis, 392 organ manifestations, 392 treatment, 389–391 Hepatitis B virus (HBV) antiviral resistance lamivudine-resistant mutants, 403 prophylactic and therapeutic strategies, 402 vaccination, 403 reactivation, antineoplastic therapy definition, 189 frequency of, 189 management of, 190 pathogenesis and clinical manifestations, 189–190 risk factors, 190 rituximab, 52 vaccine, 565 Hepatitis C virus (HCV) reactivation, antineoplastic therapy management of, 192 pathogenesis and clinical manifestations, 191–192 risk factors, 192 rituximab, 52 Hepatosplenic candidiasis, 31, 264, 276 Herpes simplex virus (HSV) antiviral prophylaxis, 527 antiviral resistance acyclovir, 398 cidofovir, 399 definition, 397–398 diagnosis, 399 leflunomide, 399 rheumatoid arthritis, 399 risk factors, 398–399 therapy, 399 toxicity, 399 Herpes viruses Epstein-Barr virus (EBV) B cell, 365 immunocompromised hosts, 365–366 transmission, 365 treatment, 366 HHV–6, 365 HHV–8, 366–367 infection phases, 359 Herpes zoster vaccine, 563–564 Histoplasma antigen, 297 Histoplasma capsulatum, 297, 485

582 Histoplasmosis antifungal therapy, 298 central nervous system, 298 clinical findings, 297 culture of, 297 Histoplasma antigen, 297 Histoplasma capsulatum, 297 immunosuppression, 297 in Nocardia pneumonia, 148–149 HLA-DR antibody, hematologic malignancies, 60 Hospital-acquired pneumonia (HAP), 146–147 Human herpes virus–6 (HHV–6), 365 Human herpes virus–8 (HHV–8), 366–367 Human metapneumovirus (hMPV) clinical presentation, 380 diagnosis, 380 immunocompromised patients, 380 Paramyxoviridae family, 379 prevention, 380 treatment, 380 Humoral immune dysfunction, hematologic malignancies, 33–34 Hydrostatic pulmonary edema, 153–154 Hypereosinophilic syndrome, 249 Hypoproteinemia, antimicrobial agents, 446 I Ibritumomab tiuxetan, 54 Idiopathic pneumonia syndrome (IPS), 159–160 IMIs. See Invasive mold infections (IMIs) Immune evasion, CMV, 342 Immune system, monoclonal antibodies interaction, 47–48 Immunocompromised traveler considerations for, 551–552 prevention, recommendations for animal bites, 556 arthropod bites, 555, 556 enteric pathogens, 552, 554–555 geographical distribution of, 553–554 respiratory pathogens, 555 sexually and parenterally transmitted infections, 556–557 skin and mucous membranes, 555–556 recommendations for, 552 vaccination in, 557 recommendations, 557–559 Immunological factors, 4–6 Immunotherapy antifungal agents, 335–336 chronic granulomatous disease (CGD), 332 cytokines, 335, 336 graft-versus-host disease (GVHD), 331, 332 host defense deficits, 331, 332 immune augmentation strategies, 333 immunologic effect, antifungals, 336 immunomodulators, 335–336 invasive fungal diseases aspergillosis and moulds, 331, 332 yeasts and dimorphic fungi, 331, 332 neutrophil number augmentation colony stimulating factors (CSF), 333–334 granulocyte transfusions, 334–335 principles and challenges, 332–333 recombinant interferon-g, 335 toll-like receptors (TLR), 335–336 Impaired humoral immunity, 523 Implantable device infections, 199

Index Infection prevention, 548 and contol, principles of, 542, 543 food and drink, 547–548 hand hygiene, 546–547 protected environment, 542–543 and PEPA, 543–546 risks, 541–542 water and moulds, 546 Infective endocarditis (IE) clinical presentation, 220–221 CoNS, 226 diagnosis and investigation antibiotics, 221 blood cultures, 221 echocardiography, 221 modified Duke criteria, 221, 222 enterococci, 227 epidemiology incidence of, 219 studies of, 219, 220 etiologic agents, 224 fungi, 227–228 management surgery, 224 treatment regimens, 222, 224 NBTE, 228–229 risk factors for, 220 Staphylococcus aureus, 224–226 streptococci, 226–227 Infliximab, 59–60 Influenza viruses antiviral resistance antiviral therapy, 401–402 diagnosis, 402 oseltamivir, 402 zanamivir, 402 antiviral resistance pattern, 375 clinical presentation, 374 diagnosis, 375 hemagglutinins (HA), 374 HSCT recipients, 374 immunocompromised patients, 374–375 leukemia patients, 374 neuraminidase (NA), 374 prevention/vaccination, 375–376 solid organ transplant patients, 375 treatment, 375 vaccination clinical studies, 564 frequency and case fatality in, 563 Innate immunity, CMV, 342 Inotuzumab ozogamicin, 57 Intensive care unit (ICU). See also Critically ill cancer patients oncologists and infectious disease specialists, 87–88 patient’s goals, 88 Intensive insulin therapy, catheter salvage, 130–131 Interferon gamma (IFN-g), 335 NTM, 463 Intestinal protozoa, 478 Intraabdominal and pelvic abscess, 197–198 Intravascular catheter-related blood stream infections (IVDR BSI) catheter salvage (see Catheter salvage, IVDR BSI) microbiology, 125 pathogenesis of mortality of, 124 percutaneous IVD, sources of infection, 124 pulsed-field gel electrophoresis, 125

Index Intravenous immunoglobulin (IVIg) BKV, 390 parvovirus B19, 392 Invasive aspergillosis (IA), 264–266 clinical data, 311–312 clinical trials, 309, 310 micafungin (MICA), 311 preclinical data, 309, 311 Invasive candidiasis, 257 Candida species in, 273 candidemia and acute disseminated candidiasis, 278–279 chronic disseminated candidiasis, 279 clinical presentation candidemia, 276 disseminated, skin lesions in, 276 endocarditis, 277 esophagitis, 276 hepatosplenic, 276 intra-abdominal infections, 277 ocular infection, 276–277 trombophlebitis, 277 urinary tract, 277 diagnosis blood cultures, 275 definitions, 275 nonculture-based methods, 275 radiological signs, 275–276 epidemiology, 273–274 mucocutaneous, 278 pathogenesis, 274 prophylaxis, 277 resistance patterns, 274 risk factors, 274–275 systemic agents, 278 treatment, 277–278 Invasive fungal disease aspergillosis and moulds, 331, 332 drugs, 257 immunopathogenesis of, 257–258 immunotherapy for, 258 sinus disease, 267–268 yeasts and dimorphic fungi, 331, 332 Invasive fungal infections (IFIs) antifungal prophylaxis, 524 diagnosis of, 261 candidiasis, 262–264 mold infections, 264–268 preemptive therapy, 287 risk factors, 284 Invasive mold infections (IMIs) amphotericin B (AMB), 285 Aspergillus fumigatus, 283 1,3-beta-D-glucan test, 284 clinical syndromes, 264 conventional diagnostic methods, 284 diagnosis of beta-D-glucan assay, 267 galactomannan antigen, 266–267 histopathology and microbiology, 265–266 imaging, 264–265 invasive fungal sinus disease, 267–268 PCR, 267 diagnostics, 283–284 echinocandins, 285–286 empiric antifungal treatment, 287 epidemiology of, 283, 284 galactomannan test, 284

583 lipid formulations, 285, 286 polymerase chain reaction (PCR), 284 posaconazole, 285 preemptive therapy, 287 prevention and prophylaxis, 286–287 radiologic methods, 284 salvage antifungal therapy, 288 second-generation triazoles, 285 therapies aspergillosis, 287–288 fusariosis, 288 phaehyphomycosis, 288 scedosporiosis, 288 zygomycosis, 288 voriconazole, 285 Invasive pulmonary mycosis. See Pulmonary mycosis Itraconazole, antifungal drug resistance, 322 J JC virus, 392, 393 K Klebsiella pneumoniae, 426 Klebsiella pneumoniae carbapenemases (KPC), 500 L Lady Windermere syndrome, 464 Lamivudine, 190 Late-onset neutropenia (LON), rituximab, 53 Leflunomide antiviral resistance, HSV, 399 BKV, 390 Leukemia acute, 34–35 neutropenic enterocolitis, 181, 182 Leukocytoclastic vasculitis, 243–244 Limb interventions, postoperative infections, 77 Linezolid, 451 Lipid formulations, 285, 286 Lipodermatosclerosis, 246 Liposomal amphotericin B (LAMB), 307, 308 Listeria monocytogenes, 435, 436, 438, 514 Listeriosis in cancer patients, 438 clinical settings, 438 clinical syndromes bacteremia, 437 brain abscess, 438 brain stem encephalitis, 437–438 CNS infection, 437 infection, in pregnancy, 436–437 meningitis, 437 neonatal period, 436–437 CNS, 436 diagnosis, 438–439 epidemiology, 436 listeriae, 436 listerial meningitis, 437 Listeria monocytogenes, 435, 436, 438 pathogenesis, 435–436 prevention, 439 rhombencephalitis, 437–438 treatment, 439 Liver flukes, 478

584 Lumiliximab, 57 Lung cancer, 40–41 interventions, postoperative infections diagnosis of, 72 etiology of, 72 incidence of, 72 prevention, 72 risk factors, 72 treatment of, 72 pneumonia, 41 Lung infiltrates, cancer patient CILI, 154–158 HSCT, noninfectious complications of early-onset, 159–160 late-onset, 160–162 hydrostatic pulmonary edema, 153–154 nonhydrostatic pulmonary edema, 154 radiation-induced lung injury, 158–159 small airway mucus impaction, 162–163 TRALI, 162 Lymphoma, 36 M Magnetic resonance imaging (MRI), hematologic malignancies, 30 Malaria prophylaxis, 555, 556 Mannose binding lectin (MBL), 109 Marantic endocarditis. See Nonbacterial thrombotic endocarditis (NBTE) Mechanical blisters, 234–235 Meningitis acute bacterial meningitis, 211 Candida, 212 chronic, 212 listeriosis, 437 non-infectious causes of, 212 viral (aseptic) meningitis, 211–212 Methicillin-resistant Staphylococcus aureus (MRSA), 70, 147, 507 Metronidazole, 451 Micafungin (MICA) antifungal drug resistance, 323, 324 antimicrobial prophylaxis, 536 invasive aspergillosis, 311 Microbiota, bacterial colonization and host immunity, 175–176 Micrococcus species, CRBSI, 119 Miliaria crystallina, 238 Miliaria rubra, 241 Mold infections. See Invasive mold infections (IMIs) Monkey pox virus, 486 Monoclonal antibodies, colon cancer, 42, 43 Monoclonal antineoplastic therapy, hematologic malignancies anti-CD2 antibodies, 58 anti-CD3 antibodies, 58 anti-CD4 antibodies, 57–58 anti-CD20 antibodies radioimmunoconjugates, 54 rituximab, 48–54 second-generation, 54, 55 anti-CD22 antibodies, 57 anti-CD23 antibodies, 57 anti-CD33 antibodies, 57 anti-CD52 antibodies, 54–56 anti-interleukin–2 receptor antibodies basiliximab, 59 daclizumab, 58–59 denileukin diftitox, 58

Index anti-interleukin–6-receptor antibodies, 59 anti-TNFa monoclonal antibodies, 59–60 HLA-DR antibody, 60 infections and complications, 49 interaction of, 47–48 Moulds, infection prevention, 546 Moxifloxacin, 451 mRNA detection, 344 Mucocutaneous candidiasis, 278 Mucosal barrier injury (MBI) and infections cytotoxic therapy-induced mucositis, 169 epithelial innate immunity, 168–169 inflammatory response, 170 neutropenia, 167–168 neutropenic enterocolitis (NE), 170, 171 primary host defence, disintegration of, 167 Mucosal impairment, hematologic malignancies, 34 Multi-drug-resistant (MDR), 423 Multinational Association for Supportive Care in Cancer (MASCC) risk-index for neutropenic patients, 98 Multiple myeloma, 35 Mupirocin prophylaxis, 127–128 Muromonab, 58 Mycobacterial infections, 8 Mycobacterium avium, 464 Mycobacterium haemophilum, 465 Mycobacterium intracellular, 464 Mycobacterium kansasii, 464–465 Mycobacterium marinum, 487 Mycobacterium simiae, 465 Mycobacterium tuberculosis, 486 biology of, 455–456 deficiencies in antimycobacterial immunity alemtuzumab, 457 bone marrow transplantation, 457 cancer therapies, 456–457 pharmacologic cancer therapy, 457 purine analogs, 457–458 risk factors, 456–457 solid tumors, 456, 457 states of susceptibility, 456 temozolamide, 458 TNF inhibitors, 458 diagnosis, 458 graft versus host diseases, 456, 458 guidelines, TB prophylaxis chemotherapy, 459–460 clinical condition risk, 459 drug interactions, 459–460 therapy, 459 T-cell defect, 457 Mycosis fungoides and cutaneous T-cell lymphoma, 243 Myeloid growth factors, 523 Myeloma, 35–36 N Neck cancer interventions, postoperative infections, 69–70 Necrolytic migratory erythema, 248 Necrotizing fasciitis, 202–203 Neoplastic disease, patient infections abdominal infections, 12 antibiotic therapy, in neutropenic patient, 7–8 bacterial infections, 7 catheter-related infections, 12–13 diagnostic evaluation of, 6–7

Index end-organ infection, 12 epidemiological factors, 4 factors in, 3 fungal infections, 8–10 history of, 3 hosts’ susceptibility, 4 immunological factors, 4–6 mycobacterial infections, 8 parasitic infections, 10–12 pathogens of, 7 pneumonia, 12 viral infections, 10, 11 Nephritis, BKV, 392 Neutropenia aHSCT epidemiology of infections, 17–18 fever, antimicrobial therapy, 19–20 antibacterial prophylaxis antibiotic prophylaxis, 522–523 high risks patients, 522 infection, 521–522 myeloid growth factors, 523 parameters affected, 522 prevention strategies, 522, 523 treatment, 523 antibiotic therapy, 7–8 antifungal prophylaxis acute myeloid leukemia (AML), 525 Aspergillus, primary, 525–526 candidiasis, primary, 524–525 chemotherapy regimens, duration of, 524 fluconazole, 524–525 invasive fungal infections (IFI), 524 posaconazole, 525 risk assessment, 524 secondary prophylaxis, 526 antimicrobial prophylaxis, 537–538 antiviral prophylaxis, 527 bacterial infections, distribution of, 96 in children, 79 epidemiology of infections bacterial pathogens in, 96, 97 Candida spp., 97 febrile episodes, nature of, 95, 96 fever, management of antibiotic regimens, 101, 102 empiric antibiotic therapy, 98–100 evaluation of response and duration of therapy, 100–101 febrile episode, ambulatory management of, 99, 100 risk assessment and risk-based therapy, 97–98 hematologic malignancies antifungal prophylaxis, 31 bacterial infections, epidemiology of, 30 candidemia, incidence of, 31 disseminated aspergillosis, 32 fungal infections, incidence of, 28, 30 hepatosplenic candidiasis, 29, 31 influenza and mucor pneumonia, 32 MRI of, 30 severe infection episodes, circulating neutrophils, 30 immune defects, 5–6 initial assessment of, 97 invasive candidiasis, 278 meningitis, 211 mucosal barrier injury and infections, 167–168 protected environment for, 5

585 risk of infection, 4 white blood cell (WBC) transfusions, 4–5 Neutropenic enterocolitis (NEC), 170, 171 CT scan findings, 183 diagnosis diarrhea, 182, 183 fever, 182, 183 epidemiology, 181–182 management, 183–184 pathogenesis of, 182 Neutrophilic eccrine hidradenitis, 241 Neutrophil number augmentation colony stimulating factors, 333–334 granulocyte transfusions, 334–335 NFGNB. See Nonfermentative gram-negative bacilli (NFGNB) Nocardia abscessus, 148 Nocardia pneumonia, 148–149 Nocardiosis in cancer patients, 440 cell-mediated immunity, 439–440 clinical syndromes, 440 diagnosis, 440 nocardia species, 439 treatment, 440 Nodular vasculitis, 245, 246 Nonbacterial thrombotic endocarditis (NBTE) incidence of, 228 vs. infective endocarditis, 229 treatment of, 229 Nonfermentative gram-negative bacilli (NFGNB) Acinetobacter baumannii, 427–428 antimicrobial stewardship, 429–430 Chryseobacterium species, 428 documented infections therapy, 429 empiric therapy, 429 frequency of infections, 426 moderate-to-high-grade bacteremia frequency, 427 Pseudomonas aeruginosa, 426–427 Pseudomonas fluorescens, 428 Stenotrophomonas maltophilia, 427 treatment, 428 trimethoprim/sulfamethoxazole (TMP/SMX), 427 Noninfectious lung infiltrates. See Lung infiltrates, cancer patient Non-neutropenic patients antibacterial prophylaxis chronic graft versus host disease (GVHD), 524 impaired humoral immunity, 523 splenectomy, 524 antifungal prophylaxis, 526–527 Nontuberculous mycobacteriosis (NTM), 149 antimycobacterial immune defense, 463 clinical characteristics, 464 immunologic susceptibility, 463–464 interferon gamma (IFN-g), 463 Lady Windermere syndrome, 464 Mycobacterium avium, 464 Mycobacterium intracellular, 464 rapidly growing mycobacteria catheter-related infections, 465–466 pneumonia, 465 skin and soft-tissue infection, 465 slow-growing mycobacteria mycobacterium avium-intracellular, 464 Mycobacterium haemophilum, 465 Mycobacterium kansasii, 464–465 Mycobacterium simiae, 465

586 Nosocomial meningitis, 211 NTM. See Nontuberculous mycobacteriosis (NTM) O Ocular infection, invasive candidiasis, 276–277 Oseltamivir antiviral resistance, influenza viruses, 402 Outpatient antibiotic therapy, 502–504 P Pancreatic panniculitis, 245 Paneth cells, 177, 178 Panniculitis cold, 245 differential diagnosis, 245 nodular vasculitis, 245, 246 pancreatic, 245 sclerosing, 246 Papulosquamous lesions dermatitis, 241–242 mycosis fungoides and cutaneous T-cell lymphoma, 243 pityriasis rosea, 243 pityriasis rubra pilaris, 243 psoriasis, 242, 243 Parainfluenza viruses (PIV) clinical presentation, 376 diagnosis, 376–377 HSCT recipients, 376 immunocompromised patients, 376 leukemia patients, 376 prevention/vaccination, 377 solid organ transplant patients, 376 treatment, 377 Paraneoplastic autoimmune multiorgan syndrome, 236 Paraneoplastic neurological syndromes (PNS), 215 Paraneoplastic pemphigus, 236, 237 Parasitic infections, 10–12 Acanthamoeba spp., 477 Balamuthia mandrillaris, 477 Chagas’ disease, 477 Cryptosporidium spp., 478 intestinal protozoa, 478 liver flukes, 478 Schistosoma spp., 478 schistosomiasis, 478 strongyloidiasis in cancer patients, 476 clinical findings, 474–475 diagnosis, 475–476 epidemiology, 474 hyperinfection prevention, 477 hyperinfection syndrome, 474 organism, 473 pathogenesis and immunity, 474 treatment, 476 toxoplasmosis clinical manifestations, 470–471 diagnosis, 471–472 life cycle and epidemiology, 469–470 management, 472, 473 prevention, 473 Trypanosoma cruzi, 477 visceral leishmaniasis (VL), 477–478 Parvovirus B19, 392, 393 Pasteurella multocida, 482

Index Pattern recognition receptors (PRRs), 168 Pelvic abscess, 197–198 Pemphigus, 236, 237 Peptide nucleic acid fluorescent in situ hybridization (PNA-FISH) test, 263 Peritonitis and intraabdominal abscess, genitourinary tract infections, 200–201 Petechiae, 245 Phaehyphomycosis, invasive mold infections, 288 Phagocyte defects, hematologic malignancies, 30–31 Pharmacokinetics antibacterial distribution, 443–444 parameters, 443–444 Pharmacokodynamic (PD) indices, for anti-infective therapy, 444 Pharmacologic cancer therapy, 457 Pityriasis rosea, 243 Pityriasis rubra pilaris, 243 PIV. See Parainfluenza viruses Plague, 484 Pneumococcal vaccine, 564 Pneumocystis jerovici pneumonia (PCP), 43, 44 Pneumocystis pneumonia, 149 Pneumonia, 11, 12 immune defects, 143 aspiration and bronchial obstruction, 147–148 community-acquired pneumonia, 146 hospital-acquired pneumonia, 146–147 infections in, 144 neutropenia, 145 neutrophils, 145 Pseudomonas lung abscess, 145 septic emboli, 148 pathogens histoplasmosis in, 148 invasive pulmonary mycosis, 150–151 nocardiosis, 148–149 nontuberculous mycobacteriosis, 149 Pneumocystis, 149 tuberculosis, 149 viruses, 151 Poliovirus, 565 Polymerase chain reaction (PCR), 284 candidiasis, 263–264 empiric antifungal therapy, 108–109 invasive mold infections, 267 parvovirus B19, 392 Polyomavirus BK virus definition, 387 hemorrhagic cystitis, 388–392 transmission and pathogenesis, 388 virologic aspects, 387–388 JC virus, 392, 393 parvovirus B19, 392, 393 Porphyria cutanea tarda (PCT), 237 Posaconazole antifungal prophylaxis, 525 clinical trials, 303 drug interactions, 302, 303 hepatic dysfunction, 303 invasive mold infections (IMIs), 285 pharmacokinetic variability, 322–323 toxicity, 303–304 Postoperative infections brain cancer, 67–68 breast cancer interventions, surgical site infections, 70–71

Index central nervous system external ventricular drains (EVDs), 214 postcraniotomy infections, 214 shunt infections, 214 in children, 77–80 esophageal cancer, 72–73 genital and urinary tract neoplasms, 75–77 GI tract interventions, 73–75 head and neck cancer interventions, 69–70 limb interventions, 77 lung cancer interventions, 71–72 surgery infections, prevention and management for, 77 Posttransplantation constrictive bronchiolitis (PTCB), 161–162 Posttransplantation lymphoproliferative disorder (PTLD), 162 Pre-emptive therapy, CMV, 346–347 Procalcitonin (PCT), 107 Progressive multifocal leukoencephalopathy (PML), 10, 209, 392 rituximab, 53 Prophylactic antibiotic programmes (PEPA) and PE airborne protection, 545 exogenous and endogenous opportunistic pathogens, 543 HEPA filtration, 545–546 patient culture specimens, 544 prophylactic topical and oral non-absorbable antimicrobials, 544 randomised trial of, 545 remission rates, 544 universal protection, 545 Prophylactic vaccination, HSCT chemotherapy, 562 eukaryotic infections, 566–567 Haemophilus influenzae type B, 564–565 hepatitis B virus, 565 herpes zoster, 563–564 immune suppression, 562 influenza, 563, 564 pneumococcal pneumonia, 564 poliovirus, 565 tumor-derived factors, dendritic cells, 561, 562 viral infections adenovirus and polyomavirus, 566 CMV and EBV, 566 respiratory viruses, 566 Protected environment (PE), 542–543. See also Prophylactic antibiotic programmes (PEPA) and PE Pseudomonas aeruginosa, 426–427, 501 Pseudomonas fluorescens, 428 Pseudomonas lung abscess, 145 Pseudoporphyria cutanea tarda, 237, 238 Psoriasis, 242, 243 Pulmonary alveolar proteinosis (PAP), 160, 161 Pulmonary edema HSCT, early-onset noninfectious complications of, 159 hydrostatic, 153–154 nonhydrostatic, 154 Pulmonary mycosis fungal infections diagnosis, 150 incidence of, 150 treatment of, 151 Pulmonary nocardiosis, lymphoma, 33 Pulmonary veno-occlusive disease (PVOD), 160 Pulsed-field gel electrophoresis, IVDR BSI, 125 Purine analogs, 457–458 Purpuric and petechial lesions calciphylaxis, 244 DIC, 244 leukocytoclastic vasculitis, 243–244

587 petechiae, 245 superficial thrombophlebitis, 244 Pustular lesions acneiform eruptions, 240 AGEP, 238 eosinophilic folliculitis, 240 Grover disease, 241 miliaria rubra, 241 neutrophilic eccrine hidradenitis, 241 reactive neutrophilic dermatoses, 239–240 Pyoderma gangrenosum, 239, 240 Q Q fever, 484 Quantitative polymerase chain reaction (qPCR), 343 R Radiation-induced lung injury, lung infiltrates, 158–159 Radiation pneumonitis, 158 Radioimmunoconjugates, anti-CD20, 54 Rapidly growing mycobacteria (RGM) catheter-related infections, 465–466 lung disease, 8 pneumonia, 465 skin and soft-tissue infection, 465 Reactive neutrophilic dermatoses, 239–240 Recombinant interferon-g, 335 Respiratory mycosis, cryptococcal disease, 294 Respiratory pathogens, immunocompromised traveler, 555 Respiratory syncytial virus (RSV) clinical presentations, 372 diagnosis, 373 HSCT recipients, 372–373 immunocompromised patients, 372–373 leukemia patients, 372–373 prevention/vaccination, 374 solid organ transplant recipients, 373 treatment, 373 Respiratory viruses acute infectious illness, 381–382 adenovirus clinical presentation, 377 diagnosis, 378 HSCT recipients, 377–378 immunocompromised patients, 377–378 leukemia patients, 377–378 prevention/vaccination, 378 solid organ transplant patients, 378 treatment, 378 coronavirus clinical presentation, 380 diagnosis, 381 immunocompromised patients, 380 prevention, 381 treatment, 381 enterovirus clinical presentation, 381 diagnosis, 381 immunocompromised patients, 381 prevention, 381 treatment, 381 human metapneumovirus (hMPV) clinical presentation, 380 diagnosis, 380

588 Respiratory viruses (cont.) immunocompromised patients, 380 Paramyxoviridae family, 379 prevention, 380 treatment, 380 infections, 371, 372 influenza viruses antiviral resistance pattern, 375 clinical presentation, 374 diagnosis, 375 hemagglutinins (HA), 374 HSCT recipients, 374 immunocompromised patients, 374–375 leukemia patients, 374 neuraminidase (NA), 374 prevention/vaccination, 375–376 solid organ transplant patients, 375 treatment, 375 parainfluenza viruses (PIV) clinical presentation, 376 diagnosis, 376–377 HSCT recipients, 376 immunocompromised patients, 376 leukemia patients, 376 prevention/vaccination, 377 solid organ transplant patients, 376 treatment, 377 respiratory syncytial virus (RSV) clinical presentations, 372 diagnosis, 373 HSCT recipients, 372–373 immunocompromised patients, 372–373 leukemia patients, 372–373 prevention/vaccination, 374 solid organ transplant recipients, 373 treatment, 373 rhinovirus clinical presentation, 379 diagnosis, 379 immunocompromised patients, 379 Picornaviridae family, 378–379 prevention, 379 treatment, 379 syndromes, 371, 372 Retinitis, CMV, 344–345 Reversible posterior leukoencephalopathy syndrome (RPLS), 215 Rheumatoid arthritis, antiviral resistance CMV, 401 HSV, 399 Rhinovirus clinical presentation, 379 diagnosis, 379 immunocompromised patients, 379 Picornaviridae family, 378–379 prevention, 379 treatment, 379 Rhizopus multicentric cavitary pneumonia, 150 Rhombencephalitis, 437–438 Ribavirin, 192 Rifamycin derivates, 450 Rituximab associated infection cytomegalovirus, 52–53 hepatitis B and C, 52 HIV1-associated conditions, 51 indications, 53–54

Index late-onset neutropenia (LON), 53 phase III randomized controlled trials, 50, 51 B-cell depletion, 49 maintenance therapy, 50 side effects of, 50 RSV. See Respiratory syncytial virus (RSV) S Salvage antifungal therapy, 288 Scalp lesions, 250 Scedosporiosis, 288 Schistosoma haematobium, 478 Schistosoma spp., 478 Schistosomiasis, 478 Septal panniculitis, 245–246 Septic encephalopathy, 209 Septic pelvic thrombophlebitis, 203–204 Serratia marcescens, 425 Sexually and parenterally transmitted infections, 556–557 Single nucleotide polymorphisms (SNPs), 168–169 Siplizumab, 58 Skin lesions, disseminated candidiasis, 276 and soft-tissue infection, 465 Skin disorders erythematous lesions chemotherapy-induced acral blisters and erythema, 248 EM/SJS and TEN, 246–247 eosinophilic dermatoses, 249 erythema annulare centrifugum, 247, 248 erythema gyratum repens, 247–248 granuloma annulare, 248–249 necrolytic migratory erythema, 248 urticaria and angioedema, 246 hair and scalp lesions, 250 panniculitis cold, 245 differential diagnosis, 245 nodular vasculitis, 245, 246 pancreatic, 245 sclerosing, 246 papulosquamous lesions dermatitis, 241–242 mycosis fungoides and cutaneous T-cell lymphoma, 243 pityriasis rosea, 243 pityriasis rubra pilaris, 243 psoriasis, 242, 243 purpuric and petechial lesions calciphylaxis, 244 DIC, 244 leukocytoclastic vasculitis, 243–244 petechiae, 245 superficial thrombophlebitis, 244 pustular lesions acneiform eruptions, 240 AGEP, 238 eosinophilic folliculitis, 240 Grover disease, 241 miliaria rubra, 241 neutrophilic eccrine hidradenitis, 241 reactive neutrophilic dermatoses, 239–240 ulcerative lesions and skin tumors, 249–250 vesiculobullous lesions acute dermatitis, 233 autoimmune bullous dermatoses, 236–237

Index bullous drug eruptions, 235–236 bullous GVHD, 235 bullous insect bite reaction, 235 diabetic blisters, 235 edema and lymphedema bullae, 235 mechanical blisters, 232 miliaria crystallina, 238 porphyria cutanea tarda (PCT), 237 pseudoporphyria cutanea tarda, 237, 238 Slow-growing mycobacteria (SGM) mycobacterium avium-intracellular, 464 Mycobacterium haemophilum, 465 Mycobacterium kansasii, 464–465 Mycobacterium simiae, 465 Solid tumor patients breast cancer, 41–42 CNS cancer, 43–44 colon cancer, 42, 43 GU cancers, 43 vs. hematologic malignancy, 39, 40 infection risks and pathogens, 39–40 lung cancer, 40–41 Mycobacterium tuberculosis infection, 456, 457 neutropenia, 39 treatment regimens, 41 Splenectomy, 524 Splenic dysfunction, hematologic malignancies, 34 Staphylococci coagulase negative staphylococci, 412 Staphylococcus aureus chest computerized tomography, 411 clinical manifestations, 410–411 diagnosis, 410–411 epidemiology, 409–411 treatment, 411–412 Staphylococcus aureus antibiotic treatment, 411 catheter salvage, 135–136 chest computerized tomography, 411 clinical manifestations, 410–411 CRBSI, 119 diagnosis, 410–411 epidemiology, 409–411 infective endocarditis daptomycin, 225–226 neutropenia, 225 TEE, 225 vancomycin, 225, 226 treatment, 411–412 Stem cell transplantation (SCT), HBV and HCV reactivation, 189–192 Stenotrophomonas maltophilia, 427 Stevens–Johnson syndrome (SJS), 246–247 Streamlining, ASP, 494 Streptococci definition, 412–413 empiric antimicrobial therapy, 417 enterococcus clinical presentation/diagnosis, 416 epidemiology, 416 treatment, 416–417 b-hemolytic streptococci clinical manifestations/diagnosis, 414 definition, 414 epidemiology, 414 treatment, 414–415

589 infective endocarditis penicillin, minimal inhibitory concentration, 226–227 Streptococcus bovis, 227 Streptococcus pneumoniae clinical presentations/diagnosis, 415 epidemiology, 415 treatment, 415–416 viridans group streptococci, 413 Streptococcus aureus, mupirocin prophylaxis, 127–128 Streptococcus pneumoniae clinical presentations/diagnosis, 415 epidemiology, 415 treatment, 415–416 Strongyloides stercoralis. See Strongyloidiasis Strongyloidiasis, 528 bronchoalveolar lavage, 476 bronchoscopic biopsy, 475 in cancer patients, 476 clinical findings, 474–475 diagnosis, 475–476 epidemiology, 474 hyperinfection prevention, 477 hyperinfection syndrome, 474 organism, 473 pathogenesis and immunity, 474 sputum, 476 treatment, 476 Sulfamethoxazole (SMX), 427 Suppurative pelvic thrombophlebitis, 203–204 Surgical infection, genitourinary tract, 200 Surgical site infections (SSIs). See Postoperative infections Sweet syndrome, acute febrile neutrophilic dermatosis, 239 Systemic catheter infections, CRBSI, 114 T TDM. See Therapeutic drug monitoring (TDM) Temozolomide, 44, 458 Therapeutic drug monitoring (TDM) parameters, 301, 302 posaconazole clinical trials, 303 drug interactions, 302, 303 hepatic dysfunction, 303 toxicity, 303–304 voriconazole blood levels, tests for, 302–303 clinical trials, 301–302 criterias, 303 drug interactions, 301, 302 hepatic metabolism, 301 toxicity, 302 voriconazole, pharmacokinetic variability, 322 Thrombophlebitis, 244 Tigecycline, 452 Tissue infections, 446–447 Tocilizumab, 59 Toll-like receptors (TLR), 335–336 Topical antimicrobials, catheter salvage, 126–128 Toxic epidermal necrolysis (TEN), 246–247 Toxoplasma encephalitis, 209 Toxoplasma gondii acute infection, 470–471 forms of, 470 zoonoses, 485

590 Toxoplasmosis, 528 clinical manifestations acute infection, 470–471 chronic infection, 471 diagnosis histological methods, 472 polymerase chain reaction, 472 serological tests, 471–472 drugs, 472, 473 invasive procedures, 472 life cycle and epidemiology oocysts, 469–470 tissue cysts, 469, 470 management, 472, 473 prevention, 473 Transfusion-related acute lung injury (TRALI), 162 Transthoracic echocardiography (TTE), 221 Travel medicine, 551 Triazoles, 318–320 Trimethoprim (TMP), 427 Trimethoprim-sulfamethoxazole, 452 Trombophlebitis, invasive candidiasis, 277 Trypanosoma cruzi, 477 Tuberculosis, 149 deficiencies in antimycobacterial immunity alemtuzumab, 457 bone marrow transplantation, 457 cancer therapies, 456–457 pharmacologic cancer therapy, 457 purine analogs, 457–458 risk factors, 456–457 states of susceptibility, 456 temozolamide, 458 TNF inhibitors, 458 diagnosis, 458 guidelines, TB prophylaxis clinical condition risk, 459 drug interactions, 459–460 therapy, 459 Mycobacterium tuberculosis, 455–456 T-cell defect, 457 Tumor necrosis factor (TNF) inhibitors, 458 Typhlitis. See Neutropenic enterocolitis (NEC) U Ulcerative lesions and skin tumors chronic leg ulcers, 250 leukemia cutis, 251 metastatic breast carcinoma, 250 Umbilical cord blood transplantation, 346 Urinary tract candidiasis, 277 infection, 199 neoplasms, postoperative infections, 75–77 Urokinase, catheter salvage, 134 Urticaria and angioedema, 246 V Vaccination HSCT (see Prophylactic vaccination, HSCT) immunocompromised traveler, 557 recommendations, 557–559

Index Valacyclovir, VZV, 363 Valganciclovir antiviral resistance, CMV, 400 CMV, 348, 349 Vancomycin, 451 Vancomycin resistant enterococci (VRE), 500 Varicella vaccine, 364, 563 Varicella zoster virus (VZV) acyclovir, 362–364 antiviral prophylaxis, 364–365, 527 antiviral resistance, 399–400 antivirals, 364 atypical generalized zoster, 362 cell-mediated, 360 clinical manifestations, 362 epidemiology, 360 hematopoietic stem cell transplant (HSCT) recipients, 360–362 HSCT, 22 humoral immunity, 363 immunodeficiency, 360 laboratory diagnosis, 362 prevention and infection control, 363–364 risk factors, 360 treatment, 362–363 vaccination, 364 valacyclovir, 363 varicella vaccine, 364 zoster vaccine, 364 Vesiculobullous lesions acute dermatitis, 233 autoimmune bullous dermatoses, 236–237 bullous drug eruptions, 235–236 bullous GVHD, 235 bullous insect bite reaction, 235 diabetic blisters, 235 edema and lymphedema bullae, 235 mechanical blisters, 232, miliaria crystallina, 238 porphyria cutanea tarda (PCT), 237 pseudoporphyria cutanea tarda, 237, 238 Viremia, BKV, 388 Viridans group streptococci (VGS), 413 Viruses aseptic meningitis, 211–212 infections, 10, 11, 566 aHSCT, 20–22 pneumonia, 151 Visceral leishmaniasis (VL), 477–478 Voriconazole blood levels, tests for, 302–303 clinical trials, 301–302 criterias, 303 drug interactions, 301, 302 hepatic metabolism, 301 invasive mold infections (IMIs), 285 pharmacokinetic variability CYP2C19, 320–321 intra-and interpatient, 321 logistic regression analysis, 321 plasma drug exposures, 321 polymorphisms, 320–321 therapeutic drug monitoring, 322 toxicity, 302 VZV. See Varicella zoster virus (VZV)

Index W Wells syndrome, 249 Wound infection, genitourinary tract infections cellulitis, 201–202 clostridial myonecrosis, 203 necrotizing fasciitis, 202–203 surgery-related, 197 Y Yeasts, 331, 332 Yersinia pestis, 483 Z Zanamivir antiviral resistance, influenza viruses, 402 Zanolimumab, 57–58 Zoonoses Bartonella henseleae, 484 bats, 486 beasts of burden, 486 Blastomyces dermatiditis, 483 Capnocytophaga canimorsus, 482 chimpanzees, 486 Chlamydia psittaci, 487 cowpox virus, 485 Coxiella burnetii, 484 Cryptococcus neoformans, 485 definition, 481 Dipylidium caninum, 484 Dirofilaria immiti, 484 epidemiology, 481–482

591 farm animals, 486 geography, 482 habits and hobbies amphibians, 487 birds, 485–487 cats, 484–485 dog bites, 482–484 fish, 487 mammals, 486 reptiles, 487 Histoplasma capsulatum, 485 home, 482 monkey pox virus, 486 Mycobacterium marinum, 487 Mycobacterium tuberculosis, 486 nonhuman primates, 486 occupations, 482 Pasteurella multocida, 482 rodents, 486 Toxoplasma gondii, 485 veterinarians, 482 Yersinia pestis, 483 Zoster vaccine, 364 Zygomycosis, 265 invasive mold infections (IMIs), 288 treatment adjunctive therapy, 309 AMB deoxycholate (dAMB), 307 animal data, 308 antifungal agents, 307 clinical data, 308–309 echinocandins, 308 in vitro data, 308